Khawaja has moved to 155 not out and Travis Head is unbeaten on 14 at Karachi's National Stadium.
As he passed 150 for the third time in his Test career, Khawaja combined with nightwatchman Nathan Lyon (38) to frustrate Pakistan's bowlers with a 54-run partnership.
After Australia resumed at 3-251, a circumspect Khawaja allowed Lyon to set the scoring pace as the pair batted for the initial 75 minutes of Sunday's second day of play.
Lyon hit five fours from 62 balls and equalled his third-highest Test score before Pakistani paceman Faheen Ashraf (2-47) struck.
Faheem bowled Lyon with a fullish delivery which the Australian attempted to whip through the leg-side - he missed, the ball cannoned into his pads, then into the stumps.
Lyon dominated his union with Khawaja, scoring 38 of the 53 runs on Sunday until his dismissal, which left Australia 4-304.
Head, the sole batsman in Australia's top eight not to reach double figures in the drawn series-opener in Rawalpindi, started brightly after cracking three cut shots to the boundary from his initial 21 balls.
Khawaja is in sight of his highest Test score of 174 against New Zealand in 2015 - his next-best is 171 against England in 2018.
In Karachi, the lefthander reached his 150 from 322 deliveries. By lunch, he'd faced 339 balls, hitting 15 fours and a six, as Australia seek a breakthrough win at the venue.
The Australians have lost five and drawn three of their eight Tests in Karachi, which is a happy hunting ground for the hosts.
Pakistan played 34 Tests at the National Stadium before losing and, overall, have 23 wins, 18 draws and just two losses at the venue.
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