The 28-year-old is eyeing a fourth century in the series and already has 648 runs in the series, the most by any Australian in a home Ashes outside Sir Donald Bradman.
Smith started and finished the day strongly. It has been a recurring narrative this summer. He plucked a sensational one-handed slips catch to reduce the visitors to 251-6, removing Dawid Malan for 62, but grew irritated as two dropped catches and a wagging tail resulted in a total of 346.
Stuart Broad, who slapped two sixes in a quick-fire knock of 31, then clean bowled Cameron Bancroft for a duck with his second delivery.
Khawaja, who entered the fray with questions over his place in the team like Bancroft, scored slowly but smartly.
The left-hander is in the midst of an unbeaten 107-run stand with Smith, having shared an 85-run stand with David Warner earlier on Friday.
Warner was undone by a pinpoint offcutter from Jimmy Anderson late in the post- lunch session, falling for 56 when he feathered an edge to the keeper.
Australia were well placed to roll England quickly but failed to take simple chances offered by Tom Curran and Moeen Ali, on 21 and 22 respectively.
Pat Cummins dismissed Moeen (30) and Curran (39) with bouncers to finish with 4-80.
Joe Root tried to unsettle Khawaja with spin from both ends. England's skipper threw Moeen the ball after eight overs, while debutant legspinner Mason Crane came on after 14 overs.
Khawaja survived the trial. Smith proved fallible when Stuart Broad twice found his edge in the 20s but the world's best batsman was otherwise in his element.