He made his first class debut for the New South Wales Blues in 2008. In the same year, he hit consecutive double centuries for the NSW Second XI—a feat never before achieved by a NSW player. 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.
Khawaja signed a contract to play for county side Derbyshire in the 2011 English domestic season. He played in four County Championship matches, averaging 39.87 with the bat and scoring a century (135) against Kent. After his county stint, he made five further Test appearances in 2011, scoring one half-century (65) against South Africa. He was dropped from Australia's Test team after the home series against New Zealand, making way for Shaun Marsh upon Marsh's return from injury.
Lancashire signed Khawaja as an overseas player for the 2014 county season for all formats. Khawaja scored 86 runs on his debut against Durham but in vain as Lancashire lost by 27 runs.
Khawaja was selected as part of the 17-man Australian squad for the 2010–11 Ashes series. During the third test, Ricky Ponting fractured his finger and Khawaja was named as a stand-by if Ponting could not recover in time. He was subsequently selected in the Australian cricket team to play England in the fifth Test against England in Sydney on 3 January 2011. On 3 January 2011, Khawaja became the 419th Australian to be presented with an Australian Cricket Test baggy greencap. Khawaja became the first Muslim and first Pakistani-born Australian player to play test cricket for Australia, and only the seventh foreign-born cricketer to do so in the last 80 years.
In his first test in over two years, he scored his maiden international century, in the first Test against New Zealand on 5 November 2015, in which he scored 174 with 16 fours and 2 sixes. He made this return in his 10th Test in the coveted number 3 position, helping Australia to an emphatic victory.
Khawaja was born in Islamabad, Pakistan, and his family emigrated to New South Wales when he was a child. He became the first Muslim cricketer to represent Australia when he made his debut in the 2010–11 Ashes series. 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. He attained his basic pilot licence before his driving licence. He was educated at Westfields Sports High School.