In September 2011, it was announced that Khan would defend his WBA and IBF light-welterweight titles in Washington DC on 10 December against Lamont Peterson (29-1-1, 15 KOs) at the Convention Center. In front of a near sell out crowd of 8,647, Peterson defeated Khan for the by split decision in a very controversial affair. Khan was docked 2 points in rounds 7 and 12 by the Referee Joe Cooper for pushing, although illegal pushing is not usually met with such harsh consequences, the HBO team picked up on this. Peterson was dropped to the canvas twice, although the first time was counted as a slip instead of a legitimate knockdown. Both fighters boxed well and two judges scored it 113–112 to Peterson, with the other 115–110 to Khan (originally announced as 114–111 to Khan). Some observers felt it was a hometown robbery as Peterson is from Washington DC, while many felt that Khan wasn't treated fairly.

On 6 October 2009, Frank Warren confirmed that Khan would defend his WBA light welterweight title against undefeated Ukrainian American boxer Dmitry Salita (30-0-1, 16 KOs), the mandatory challenger, on 5 December, at the Metro Radio Arena in Newcastle upon Tyne, England. Due to Khan being a practising Muslim and Salita being an Orthodox Jew, the fight was hyped as a religious clash by the media, referring to it as a "battle of faiths" or "holy war", though Khan and Salita have both denied such claims. On 5 December 2009, Khan defeated Salita in 76 seconds, winning by TKO in the first round. Salita was knocked down three times, the first time after just 10 seconds into the fight. It was the first ever loss of Salita's career.

It was announced on April 8, 2009 Khan would move up to the light welterweight division to fight Andreas Kotelnik (31-2-1, 13 KOs) at the MEN Arena in Manchester for the WBA light welterweight title on 18 July. Khan Said, "This is the best news that I could have received. To fight for the world title in only my 22nd fight and at the age of just 22 is fantastic. Frank has done a great job getting the world title fight for me in Britain and now I have to go out win it." This would be Kotelnik's fourth title defense. Khan won by a unanimous decision, 120–108, 118–111, 118–111, in front of 10,000, and became the third-youngest Brit to win a world title, at the age of 22. Khan's lightning hand speed and fitness gave him the advantages to go well ahead on points in the first ten rounds. Kotelnik rallied in the closing rounds but could not land a decisive punch on Khan, Kotelnik throwing everything he had in the final two stanzas. After the fight, Khan said, "It's the best feeling ever. I want to thank Freddie Roach and my team for making this happen. I'm a world champion and I'm going to enjoy it. I'm still young and I've got big things to come."

Following his victory over Molina, Khan returned to the UK, for a fight against 33 year old Julio Díaz (40-7-1, 29 KOs) on 27 April 2013 in a 143 lbs 'catch-weight' bout. The fight took place at the Motorpoint Arena in Sheffield. Khan was able to control some of the fight and managed to survive a fourth-round knockdown from Diaz. Khan managed to hold on throughout the fight to go onto win the fight by a fairly close unanimous decision. The scorecards; Phil Edwards 114–113 – Steve Gray 115–113 – Terry O'Connor 115–112. In the aftermath, Khan praised Díaz, He caught me while I was off balance, and I couldn't get my stance back. I went down. I kept moving to recompose myself. That's what happens. There are little things to work on when we go back in the gym." Khan stated the fight could be his last in the UK.

The fight generated a live gate of $7,417,350, according to figures released by the Nevada State Athletic Commission. That total came from 13,072 tickets sold, far short of a sellout. The Alvarez-Khan gross places it 34th-best in Nevada history. On pay-per-view, the fight sold around 600,000 PPV buys and grossed about $30 million. This made it one of the biggest recent PPV fights, behind Miguel Cotto vs. Canelo Álvarez, and surpassing Manny Pacquiao vs. Timothy Bradley III and Floyd Mayweather Jr. vs. Andre Berto.

In early 2016, it was announced that Khan is moving up two weight divisions to middleweight, to fight Saul "Canelo" Álvarez (46-1-1, 32 KOs) for his lineal, Ring and WBC world middleweight championship titles. The fight took place on 7 May 2016, at the new T-Mobile Arena in Las Vegas. The bout was on HBO PPV. Golden Boy Promotions expected the fight to bring in 2 million PPV buys. Canelo was likely to be getting a career payday against Khan because this is a fight that will almost surely bring in more PPV buys on HBO than Canelo's last fight against Miguel Cotto last November. That fight brought in 900,000 PPV buys on HBO. Khan eventually lost to Álvarez by way of knockout in Round 6. Although many believe Khan was ahead on points including ESPN, two of the ringside judges had Canelo ahead after five round (49-46 & 48-47), the third judge had Khan ahead (48-47). With the scorecards heading towards a split decision halfway through the fight, Khan admitted, "it may have been a blessing being knocked out in the 6th round, rather than an upset loss on the scorecards after 12 rounds. According to CompuBox, Alvarez landed 64 of 170 (38 percent) and Khan landed 48 of 166 punches (29 percent), though only one of their shots really mattered.

Khan began to box competitively at the age of 11, with early honours including three English school titles, three junior ABA titles, and gold at the 2003 Junior Olympics. In early 2004 he won a gold medal at the European Student Championships in Lithuania, and in South Korea several months later he won a world junior lightweight title after fighting five times in seven days. One of his notable early amateur fights was against Victor Ortíz, whom he defeated in a second round stoppage. Overall, he compiled an amateur record of 101–9.

Khan has past and present involvements in supporting charitable and community causes. After the 2004 Indian Ocean tsunami, he was among those who raised money for its victims, and in the following year he visited Pakistan to dispense food in a camp set up after the Kashmir earthquake. He has also been involved with a campaign that promotes child safety around British railways, one that seeks improvements to the Criminal justice system, and another that encourages men to play a role in ending violence against women.

Khan was a 2005 nominee for the Laureus World Sports Award for Breakthrough of the Year. He was a nominee for the 2011 BBC Sports Personality of the Year Award after defeating Zab Judah.

Khan was also summoned to appear in court in Rochdale on 26 October 2007, accused of travelling in excess of 140 mph on the M62 motorway on 31 December 2006. He failed to appear and the case was adjourned to 2 November 2007, with the District Judge warning that he would issue an arrest warrant if the accused did not appear by then. He was also charged with not producing his driving licence and insurance certificate. On 7 January 2008, Khan was fined £1000 and banned for 42 days for the speeding offence.

Following his defeat to Prescott, Frank Warren sacked Khan's trainer Jorge Rubio and replaced him with Freddie Roach. Khan began training with Roach in the United States, where he sparred with then WBC lightweight champion and pound-for-pound champion Manny Pacquiao, who is also being trained by Roach. On 6 December 2008, Khan recorded a comeback win against Oisin Fagan in a second-round stoppage. With victory, Khan won the vacant WBA International lightweight title. Khan knocked Fagan down twice in the first round and Fagan's corner threw in the towel in the second, after being knocked down again.

On 12 July 2009, Khan was once again involved in a motoring incident, this time a collision with a young Cyclist. However, no action was taken against Khan after police concluded that he was not to blame for the incident in Moor Lane, Bolton, following interviews with a number of witnesses.

Maidana (29-1, 27 KOs), after failing to challenge undefeated WBO junior welterwight champion Timothy Bradley, postponed the fight to June 19 due to a back injury suffered by Maidana. On 3 May, Maidana pulled out of the fight yet again, still citing his back as the Problem. The fight had already been rescheduled from 19 June to 17 July, and Bradley went on to fight Luis Carlos Abregu on 17 July, instead of Maidana. After failing to secure the fight with Bradley, Maidana's camp announced that he would fight former-WBO junior welterweight champ DeMarcus Corley, on 28 August 2010 at the Luna Park Stadium in Buenos Aires, Argentina. Maidana went on to go and win by unanimous decision. Khan was looking for a good opponent to next challenge him for his title. One of his possible opponents was Lightweight Champion Juan Manuel Marquez. Marquez decided not to move up in weight and stayed at lightweight. Maidana then stated his intention to fight Khan: "Stop looking for possible opponents for next Khan 11 December in England. Stop looking for lightweight boxers and face the real 140-pounders. I'll go to Khan's home soil to take the other portion of the WBA title that belongs to me." The fight was confirmed on 16 September to take place at the Mandalay Bay in Las Vegas on 11 December. Khan was reported to earn at least $1.5 million compared to Maidana who had a purse of $550,000.

In August 2011, Khan began chasing a big money fight with Floyd Mayweather Jr. possibly for 2012. Mayweather Promotions boxer Jessie Vargas (16-0, 9 KOs) began calling out Khan for a potential fight. Speaking to Fighthype.com, Mayweather said, "Jessie Vargas wants to know why Amir Khan is ducking and dodging. He's asking for him. Everybody is ducking and dodging him. He's my fighter and he wants [Khan]." Speaking on a radio show, Vargas said, "He keeps saying he wants to fight Floyd. If he really wants to fight Floyd then he has to fight me first." In respect to Vargas, Khan hit back stating, "Never heard of Jessie Vargas until Floyd Mayweather mentioned that I have to fight him. He looks good, yes, but only has 16 fights. He's a prospect and I'm a unified world champion. If Jessie Vargas fights and gets past Marcos Maidana - then I'll fight him. Like Floyd said - 'you have to earn it.'

On 29 January 2012, Khan became engaged to Pakistani-American student, Faryal Makhdoom of Staten Island, NY. A thousand friends and family were in attendance, including boxer Ricky Hatton. The couple finally married on 31 May 2013 at the Waldorf Astoria in New York City. The couple then flew back to Khan's hometown of Bolton where a second celebration, a traditional Walima, took place in Manchester, which included 4,000 guests. Their first child, a daughter named Lamaisah, was born on 23 May 2014.

In January 2013, he was nominated for the Best at Sport award at the British Muslim Awards.

In 2014, he was given Pride of Performance from the President of Pakistan.

In 2015, he received an honorary degree from the University of Bolton for his contributions to sport and charity.

In 2016, Khan announced that he, along with Super Fight League, would introduce India's first team-based MMA league, with events expected to be held in India, the United States, Canada, and Dubai.

In 2017, Bill Dosanjh and Khan founded Super Boxing League after Super Fight League first season. The league is organized with the support of World Boxing Council and Professional Boxing Organisation India. The first season had 8 teams comprising both men and women pugilist.

On 10 January 2018, during a live press conference in London, Khan signed a three-fight deal with Eddie Hearn at Matchroom Sport. The deal meant Khan would fight exclusively on Sky Sports, with his return bout in the UK taking place on 21 April at the Echo Arena in Liverpool. on 29 January, Canadian boxer Phil Lo Greco (28-3, 17 KOs) was announced as his opponent. At the official press conference on 30 January, a brawl broke out after Lo Greco said, "After the Canelo loss you went on a losing streak - family, wife and then you go out and tweet to the heavyweight champion of the world. What is wrong with you, mate?" Referring to Khan's personal life. Khan responded by throwing his glass full of water towards Lo Greco. The bout would be fought at a catchweight of 150 pounds, as requested by Lo Greco's team. On 17 March, it was reported that Khan's trainer Virgil Hunter had been hospitalized due to a health scare, however was recovering well. Khan later revealed he would train with Joe Goosen for the fight. On 2 April, ESPN confirmed they would pick up the bout on their new app ESPN+, a $4.99 per month subscription streaming Service, launching on 12 April.