On 2 January 2006, The Great Khali became the first Indian professional wrestler to be signed to a contract by World Wrestling Entertainment (WWE).
With Daivari as his manager, Khali debuted on WWE television on the 7 April 2006 episode of SmackDown!, attacking The Undertaker and leaving him defenceless during his match with Mark Henry, and thus causing a no-contest ruling. Daivari explained that he now finally had a client that would destroy The Undertaker (after Muhammed Hassan and Mark Henry had previously failed). Khali made his in-ring debut on the 21 April edition of SmackDown!, defeating Funaki.
On the 12 May edition of SmackDown!, Khali was John "Bradshaw" Layfield's hand-picked opponent against World Heavyweight Champion Rey Mysterio. Khali had a height advantage of two feet and a weight advantage of 250 pounds, and defeated Mysterio in a squash match. In his match against The Undertaker at Judgment Day, Khali defeated The Undertaker with a kick to the head after receiving some illegal help from Daivari. Khali continued on a rampage for several weeks, winning handicap matches, beating superstars up in a display of power, and mocking The Undertaker's signature pin and victory pose.
Khali then challenged The Undertaker to a Punjabi Prison match at The Great American Bash. However, Khali was not medically cleared to compete in the match, and was instead replaced by Big Show, who would end up losing to The Undertaker despite interference from Khali. After he was medically cleared, Khali would be challenged by The Undertaker to a Last Man Standing match at SummerSlam. The match was moved to the SmackDown! just prior to SummerSlam and was won by The Undertaker, giving Khali his first definite loss in WWE
Daivari and The Great Khali were moved to the ECW brand officially when they made their ECW debuts on the 31 October 2006 edition of ECW on Sci Fi. Daivari beat "The Reject" Shannon Moore in a very quick match. Daivari's original theme music was used as well as his Persian rants on the microphone. Afterwards, Moore was manhandled by The Great Khali. Daivari continued his ECW winning streak over the next several weeks with The Great Khali usually following up the contest with a chokebomb on Daivari's opponent. At December to Dismember, Daivari got a victory over Tommy Dreamer following a roll-up. Dreamer then chased Daivari backstage; The Great Khali appeared and caught Dreamer, planting him on the steel ramp with a chokebomb.
On the 8 January episode of Raw, Jonathan Coachman announced that Khali had signed with Raw (without his manager Daivari), and would wrestle John Cena in the main event. Khali won by disqualification after Cena took a steel chair held by Armando Estrada and hit Khali with it. After the match, Khali chokeslammed Cena to the mat and left the ringside area, leaving Cena prone to an attack by Umaga.
On the 19 February edition of Raw, Khali demanded better competition after easily defeating The Highlanders. Four days later on SmackDown!, Khali interfered in a Falls Count Anywhere Money In The Bank qualifying match between Kane and King Booker. Khali cost Kane the match, leading to a feud which would culminate with a match at WrestleMania 23. In his first appearance at WrestleMania, Khali defeated Kane at WrestleMania 23 after slamming him with the Khali Bomb. Right after the match, Khali choked Kane with a hook and chain.
On the 30 April edition of Raw, Khali attacked Shawn Michaels, Edge, and Randy Orton (all three top contenders to the WWE Championship at the time) backstage. He then attacked WWE Champion John Cena as well, sending a message that he wanted Cena's title. The next week on Raw, Khali defeated Michaels in a No. 1 contender's match for the WWE Championship at Judgment Day. At the event, Khali lost via submission for the first time ever, tapping out to John Cena's STF. However, at Judgment Day, Khali's foot was under the rope when he tapped out, which went unnoticed by the referee. The next night on Raw, Khali expressed his outrage over the outcome via his newly established translator and manager, Ranjin Singh. At One Night Stand, Khali lost to John Cena after he was Aditude Adjustment off a crane bed. This would be the first time that The Great Khali had ever been pinned in a singles match.
On the 11 June edition of Raw, as part of the 2007 WWE Draft, Khali was drafted from Raw to SmackDown! as SmackDown!'s first draft pick. He would soon enter a feud with Dave Batista in July. The two were scheduled for a match at The Great American Bash, however, because Edge vacated the World Heavyweight Championship due to an injury, a twenty man Battle Royal was held for the title on the 20 July edition of SmackDown!. Khali won after eliminating both Kane and Batista in one move, winning his first World Heavyweight Championship. Khali dominated and defeated both Batista and Kane in a Triple Threat match that same week at The Great American Bash. Khali then debuted a new finisher called the "Khali Vise Grip" which he used to wear down Ric Flair, Batista, and Kane. At SummerSlam, Khali lost by disqualification when he used a steel chair but retained the title.
Khali then began a feud with Rey Mysterio after Mysterio won a "Championship Competition" making Mysterio the No. 1 contender. On the September 7 edition of SmackDown!, after Mysterio defeated Chavo Guerrero in an "I Quit" match, Khali applied his Vice Grip on Mysterio until Batista came to the rescue. After the assault, General Manager Theodore Long informed Khali that he would be defending his World Heavyweight Championship against both Rey Mysterio and Batista in a Triple Threat Match at Unforgiven, which Khali lost to Batista after receiving a spinebuster. Khali challenged Batista to a rematch in a Punjabi Prison Match at No Mercy in which Khali lost by failing to escape the Punjabi Prison before Batista.
In late 2007 and early 2008, Khali was put in a program with Finlay usually trying to assault Hornswoggle but with Finlay stopping him. Khali participated in a Elimination Chamber match at No Way Out, which was won by The Undertaker. At WrestleMania XXIV, Khali participated in a twenty-four man battle royal in which the winner would receive a title match against the ECW Champion Chavo Guerrero later that evening. Kane won the battle royal and went on to win the title. Khali then began a short feud with Big Show. The feud culminated with a match at Backlash where Big Show emerged victorious.
In July, Khali feuded with Triple H over his WWE Championship. On the 25 July edition of SmackDown!, Khali won a battle royal also involving Big Show, Jeff Hardy, Mr. Kennedy, Umaga and Montel Vontavious Porter, to earn the right to face Triple H at SummerSlam. At the event, Khali lost to Triple H after receiving a Pedigree. Khali was given another opportunity to win the WWE Championship, when he faced Jeff Hardy to gain entry into the Championship Scramble at Unforgiven. Triple H interfered in the Scramble qualification match, and aided Jeff Hardy with a chair shot to Khali, helping Hardy win and eliminating Khali from title contention.
Khali grew to take on a more "fun" persona; he and Ranjin Singh began hosting the weekly "Khali Kiss Cam", where Singh would summon ostensibly random women from the audience to kiss Khali.
The Great Khali feuded with Dolph Ziggler, winning by disqualification after Ziggler attacked him with a steel chair. In the next few weeks, Khali lost to Ziggler by countout and disqualification after Ziggler made it look like Khali hit him with a steel chair. At The Bash, Khali lost to Ziggler by pinfall, after Kane returned and attacked Khali. It was later revealed that Ranjin Singh was the Khali's brother. The feud with Kane resulted in a match at SummerSlam, where Kane defeated Khali after Kane used Singh as a distraction, and performed a running DDT to Khali. Then Khali lost to Kane again at the first ever WWE Breaking Point event.
Khali required knee surgery, so Kane "assaulted" Khali with the ring steps during a match so Khali could have time off. Whilst injured, Khali made a surprise appearance alongside Ranjin Singh, Ozzy Osbourne and his wife Sharon on the 2 November edition of Raw, as a judge for the "Raw's Got Talent" segment. He made his official return on the 14 December edition of Raw teaming with Kane and Christian to defeat William Regal, Ezekiel Jackson and Vladimir Kozlov.
On the 2 April edition of SmackDown, it was announced that Khali would be out of action for an undefined amount of time as he needed to spend time with his family and regroup his thoughts back in India. However, on the 19 April edition on Raw, he made an appearance by teaming up with special guest host MacGruber in a 2-on-1 handicap match against Vladimir Kozlov as "Khaluber" (Khali dressed as MacGruber) which they won by intentional count-out.
As part of the 2010 WWE Supplemental Draft, Khali and Ranjin Singh were both drafted back to the Raw brand. After returning from his hiatus the previous month, Khali was announced by John CenaJohn Cena to be a part of his team along with John Morrison, Chris Jericho, Edge, R-Truth and Bret Hart to face The Nexus at SummerSlam. On the 9 August episode of Raw however, Khali was assaulted and injured by The Nexus, thus removing him from the match. Following the attack, Khali then took another hiatus to compete in Bigg Boss, in which he was the runner up on. He made his return at the 2011 Royal Rumble though he was eliminated shortly by Mason Ryan. On the 14 March episode of Raw, after Khali defeated The Miz by disqualification, Miz would assault Khali with a steel chair, which resulted in Khali suffering an injury. Khali won an interbrand dark match battle royal at Wrestlemania XXVII.
On 26 April, Khali was drafted to back to SmackDown as part of the 2011 Supplemental Draft. Khali returned on the 29 April edition of SmackDown, talking backstage with Jinder Mahal, who made his WWE debut that night. On the 2 May episode of Raw, Khali dressed up as the Tooth Fairy at The Rock's birthday party.
On the 6 May edition of SmackDown, Mahal, unimpressed by how Khali and Ranjin Singh have been partaking in childish activities instead of winning matches, confronted Singh about his mismanagement of Khali. Mahal then interrupted a Khali Kiss Cam segment the following week, slapping Khali twice. On the 20 May edition of SmackDown, Mahal interrupted Khali's match against Jey Uso, which lead to Khali leaving the ring to confront Mahal. Mahal would then slap Khali again, which made Khali re-enter the ring and defeat Jey Uso, and then assault Jimmy Uso after the match.
On the 27 May edition of SmackDown, after being defeated by Kane, Mahal came out and shoved Ranjin Singh. Khali then used his vice-grip on Singh, turning heel in the process and forming an alliance with Mahal. Khali from then on acted as Mahal's bodyguard, assaulting Mahal's opponent's after his matches. On the 1 July edition of SmackDown, Ranjin Singh revealed that Mahal was their brother-in-law and that if Khali didn't obey Mahal, then he would divorce Khali's sister and put his family back into poverty. On the September 9 edition of SmackDown, Khali and Mahal went against WWE Tag Team Champions Air Boom (Evan Bourne and Kofi Kingston) in a losing effort after Khali pushed Mahal, allowing Kingston to hit his Trouble in Paradise finishing move onto Mahal. After the match, Khali would walk away from Mahal, thus, turning face again. Khali would face Mahal on the 23 September edition of SmackDown, in which he successfully beat Mahal.
On the 30 September episode of SmackDown, Khali was defeated by World Heavyweight Champion Mark Henry. After the match Henry (kayfabe) fractured Khali's fibula with a steel chair. Khali then returned to India for a few months for charity work and artistic pursuits.
On 29 January 2012, Khali returned to WWE at the WWE Royal Rumble 2012 pay-per-view as the number 15 entrant in the Royal Rumble match, eliminating Ezekiel Jackson and Jinder Mahal before being eliminated by Cody Rhodes and Dolph Ziggler. He returned on the 3 February episode of SmackDown, saving Justin Gabriel from Rhodes, Hunico, and Hunico's bodyguard Camacho. Later the same night, Khali was announced as the replacement to Mark Henry in the SmackDown Elimination Chamber match for the World Heavyweight Championship at the WWE Elimination Chamber 2012 pay-per-view. On the February 6 edition of Raw, Khali teamed up with Randy Orton in a winning effort against Rhodes and Wade Barrett. After the match, Khali and Orton got into an argument which led to Khali being hit with an RKO. On the February 10 edition of SmackDown, Khali defeated Jinder Mahal, winning his first singles match since returning. On the February 17 edition, Khali teamed up with the Big Show in a winning effort against Rhodes and Barrett. After the match, Big Show knocked out Khali with a W.M.D. At Elimination Chamber, Khali failed to capture the World Heavyweight Championship after being eliminated first by Big Show. On the March 23 edition of SmackDown, The Great Khali was added to Theodore Long's WrestleMania XXVIII team. In July, it was announced that Khali was undergoing surgery for a benign tumor found in his pituitary gland due to acromegaly. Khali returned at the SmackDown tapings on October 16, in a match taped for WWE Saturday Morning Slam. Khali finally returned to television on the November 2 episode of SmackDown, defeating David Otunga. On the November 16 episode of SmackDown, Khali competed in his first main event in years, losing to World Heavyweight Champion Big Show in a non-title match. On the December 26 episode of WWE Main Event, Khali won a 20-man battle royal to become the number one contender to the United States Championship. Khali received his title shot the following week on the January 2, 2013, episode of Main Event, but was defeated by defending champion Antonio Cesaro. On the 11 January episode of Smackdown, Khali and Natalya accompied by Hornswoggle lost to Dolph Ziggler and AJ Lee in a mixed tag team match, where after the match Khali and Hornswoggle was assaulted by Big E Langston.
On the 12 February episode of WWE Raw, Khali lost to the returning Mark Henry as Henry attacked Hornswoggle after the match, setting up a feud between the two. In late 2013, he began teaming with Santino Marella and resumed being managed by Hornswoggle after they defeated Heath Slater and Jinder Mahal on the September 27th episode of SmackDown. At WWE Battleground they were defeated by Antonio Cesaro and Jack Swagger.
On April 6, 2014, at WrestleMania XXX, Khali participated in the Andre the Giant Memorial Battle Royal, but was eliminated by 3MB. On the June 30th episode of Raw, Khali was announced as a participant of the WWE Intercontinental Championship battle royal at WWE Battleground and defeated Damien Sandow dressed as Vince McMahon. On the 31 October episode of SmackDown Khali had his final match with WWE, losing to Rusev.
On 13 November 2014, Khali's contract expired and he left WWE.