Khawaja made his first-class cricket debut for New South Wales in 2008 and played his first international match for Australia in January 2011.

He is a qualified commercial and instrument-rated pilot, completing a bachelor's degree in aviation from the University of New South Wales before he made his Test debut.

[8] In December 2023, during a training session for Australia's first test match of the series against Pakistan, Khawaja wore shoes on which the words "All lives are equal" and "freedom is a human right" were written in the colours of the Palestinian flag.

[14][15] [16] Khawaja made a post on Instagram using the hashtags “#inconsistent and #doublestandards,” in which he pointed out several examples of other cricketers with symbols on their bats, such as ‘Om’ sticker for a Hindu player, or Bible verses and crosses for others.

[21] On 22 June 2010 it was announced by Cricket Australia that Usman Khawaja would be a part of the Australian touring squad to play Pakistan in a two Test series in England.

[35] Before the third Test against India in March 2013, Australia suspended Khawaja, along with James Pattinson, Shane Watson and Mitchell Johnson following a breach of discipline.

[36] Michael Clarke, the captain, revealed that the step had been taken as a result of repeated infractions which led to Watson flying back home and contemplating Test retirement.

[40] During the 2015–16 season, Khawaja was in spectacular form for Australia and his domestic T20 franchise the Sydney Thunder, with many pundits hailing his renaissance as a batsman since being dropped from the Australian team in 2013 and recovering from an injury in 2015.

[41] In August 2016, Khawaja endured one of the lowest ebbs in test career when he was dismissed twice in a day's play for 11 runs and duck in both innings by Dilruwan Perera during Australia's second test match of the series against Sri Lanka at Galle International Stadium and question marks were raised about Khawaja's inability to play spin especially in subcontinental conditions.

[42] His vulnerability against spin also played a major reason in removing him from the side ahead of the third and the final test match of the series.

[47][48] He showed his glimpses of using proper technique and shot selection to counter the spin attack in the test match in Dubai in 2018 which turned out to be a turning point in his career and he buried the past nightmares of being a weak batsman against spin with a prolific batting effort by revamping his approach in both innings to save the test match for Australia from a brink of huge defeat.

[50][51] In Australia's final group-stage match, against South Africa, Khawaja picked up a hamstring injury, ruling him out of the rest of the tournament.

[55] Therefore, for the fourth Ashes Test, Steve Smith replaced Khawaja after returning from concussion, while Marnus Labuschagne retained his place in the side.

[56] On 16 July 2020, Khawaja was named in a 26-man preliminary squad of players to begin training ahead of a possible tour to England following the COVID-19 pandemic.

[63] Khawaja capped off his return to international cricket by picking up the Shane Warne Test Player of the Year at the Allan Border Medal ceremony, ahead of Travis Head and Steve Smith.

[67][68] Khawaja was also triggered by interesting field placement strategy deployed by England captain Ben Stokes which made him to throw his wicket away possibly at a critical juncture of the match.

Khawaja again made runs in the second innings which was critically important in the context of the match where Australia were set a challenging target of 282.

His innings eventually sealed the deal for Australia as the visitors won the closely fought contest by margin of 2 wickets courtesy of late cameos from skipper Pat Cummins and Nathan Lyon.

[69] He was awarded the player of the match for his batting heroics in the first test which guided Australia to take an early lead in the Ashes series 1-0 thereby having a psychological advantage over the home side.

[72] He alongside his opening partner David Warner had engaged in an heated exchange with MCC members as the Australians went to their dressing room at lunch session.

[73] He further elaborated that certain people in the crowd brought about his past failures and struggles in English conditions when he was part of Aussies side in 2013 and 2019 for the Ashes series down under.

Khawaja had endured a lean patch of form during Australia's five-match home test series against India having mustered only 184 runs in across 10 innings with a low average of 20.44 and only managed to score a solitary half-century.

[82][83] He eventually scored his maiden double century in test cricket and became the second oldest ever Australian test cricketer to score a double century at the age of 38 years and 42 days, trailing only behind Aussie great Don Bradman who did it at the age of 39 years and 149 days.

He also shattered the record held by Michael Slater's innings of 219 for the highest individual score by an Australian batsman against Sri Lanka in test cricket with 232.