Earlier, Dawid Malan (140) and Jonny Bairstow (119) both posted centuries after England resumed on 305/4 and produced the most productive partnership of the series for the tourists before another late collapse. Smith dominated the 124-run stand with Khawaja and will resume Saturday with Shaun Marsh on 7 not out.
England struck back with the ball through fast bowler Craig Overton (2/46), having Warner caught behind and then successfully reviewing an lbw decision against Bancroft after it was initially rejected. Overton left the field later with a suspected side strain. Medium paceman Chris Woakes, who replaced Overton at the crease, trapped Khawaja lbw.
Steve Smith countered an early loss of Australia's opening batsmen with a dominating 92 not out as the home side responded positively to England's 403 all out in the third Ashes Test at the WACA on Friday. After England had collapsed from 368/4, losing its last six wickets for 35 runs, Australia lost David Warner (22) and Cameron Bancroft (25) in quick succession and slumped to 55/2.
Needing to avoid defeat in Perth to have any chance of salvaging the five-match series, England won the toss and produced its most positive innings of the tour after heavy losses in the first two Tests in Brisbane and Adelaide.