After earlier reaching his first test century in more than a year, Khawaja continued his revival to be 166 not out at the interval.
Shaun Marsh unbeaten on 54, sharing a 91-run fourth- wicket partnership as England bowled with good discipline after lunch to restrict Australia's scoring opportunities.
Khawaja raised his 150 off 333 balls, with 16 fours and a six, with consecutive boundaries off Moeen Ali. His milestone drew warm appreciation from a capacity Sydney Cricket Ground cloaked in pink to support the McGrath Foundation breast cancer charity fundraiser, which is in its 10th year.
Australia took the lead 15 minutes before tea with Marsh playing a cover drive for a boundary to surpass England's first innings total of 346.
Shortly after, he reached his half-century from 121 balls with consecutive boundaries off Jimmy Anderson.
With the hosts placing a high value on defending their wickets, chances were few and far between for England in the middle session.
Captain Joe Root appeared to have given the first breakthrough of the afternoon in the 115th over removing Shaun Marsh caught behind when on 22. Marsh immediately requested a review and the TV replays showed that the ball had missed the bat and the out decision was reversed.
The pair almost batted through a second consecutive session only for Ali to get the prize breakthrough of Smith moments before the lunch interval and deny the Australia captain another century that would have matched Bradman's 1930 feat of scoring four hundreds in an Ashes series.
England face the likelihood of a large first-innings deficit, despite a strong rally on Friday morning by their lower order which lifted the tourists to a competitive 346, after it had slumped to 233-5 when it lost its last specialist batsman, Dawid Malan (62), early in the session.
Australia won the first three Tests convincingly to regain the Ashes, and the fourth test was drawn last week in Melbourne.
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