The Australian skipper became the second fastest batsman to reach 6,000 Test runs in his 111th innings, second only to the legendary Don Bradman.
Smith, with three centuries in this five-match series, has been the bane of the England team and was potentially heading towards another ton.
At the close, Smith was on 44 with Khawaja reaching his highest score of the series on 91 in Australia's 193 for two in reply to England's 346 first innings.
So far in the series Smith has scored 648 runs at 162.
The pair shared in a 107-run partnership after the loss of openers Cameron Bancroft and David Warner.
Khawaja raised his third fifty of the series with a six down the ground off Moeen Ali.
Debutant Mason Crane, the youngest specialist spinner at 20 to play for England in 90 years, troubled Smith and Khawaja with his wrist spin, enticing some edges and false shots to finish with no wicket for 58 off 17 overs.
Warner reached his fourth half-century of the series before James Anderson coaxed an edge to wicketkeeper Jonny Bairstow for 56 after Bancroft was bowled by Stuart Broad for a seven-ball duck.
England's maligned tail earlier piled on runs before the tourists were bowled out at lunch.
Newcomer Tom Curran smacked 39 off 65 balls, Moeen Ali hit 30 and Broad clubbed two sixes in his 31 off 32 balls as England lashed out late in the extended morning session.
Smith pulled off a stunning one-handed catch to dismiss Dawid Malan for 62, but the Australians were guilty of two embarrassing dropped catches to give England a helping hand.
The Australian skipper made an athletic diving catch to end the dangerous batsman's innings at second slip off Mitchell Starc.
Malan, who hit a century in the third Perth Test, has scored 378 runs at 47.25 in the series, second only to Alastair Cook for England.
But Australia then dropped two regulation catches in the space of four balls.
Pat Cummins put down Curran on 21 at mid-on off Nathan Lyon then in Cummins' next over Josh Hazlewood made a dreadful hash of a skied catch at mid-on from Moeen on 22.
It was the 11th dropped catch by Australia's fielders in the series, with five coming off Lyon's bowling.
But Cummins made partial amends when he had Moeen caught off his glove to a lifter for 30, giving wicketkeeper Tim Paine his fourth catch of the innings.
Broad and Curran hit out late in the session with Broad clubbing Cummins for two sixes to the delight of England's Barmy Army supporters.
Curran finally fell to a bat-pad catch by Bancroft for 39 off 65 balls to give Cummins his fourth wicket.
Broad went for another heave on 31, only to top-edge behind the wicket for Smith to take the catch and give spinner Lyon his only wicket.
Australia have already clinched the Ashes with an unassailable 3-0 lead in the five-Test series.
Ashes 2017australiaDavid WarnerDawid Malandon bradmanEnglandJonny Bairstowmason craneMoeen Aliscgsteve smithsydneySydney TestUsman Khawaja
First Published: January 5, 2018, 1:36 PM IST