After winning the toss and batting in the third and final Test in Jamaica, Australia were all out for 225 before the hosts went to stumps on night one at 1-16.
Steve Smith led the way for Australia with a stylish 48 before a loose shot paved the way for a collapse of 7-68, as the tourists' pursued quick runs in the final session.
Mitchell Starc then struck late, bowling debutant Kevlon Anderson for three with West Indies' two first-choice openers Mikyle Louis (knee) and John Campbell (shoulder) away getting scans.
It came as Australia's selectors delivered Saturday's biggest bombshell, dropping Nathan Lyon for a Test for the first time in 12 years.
Still it is the questions at the top of the order that will attract the most interest in Australia's last Test before this summer's Ashes.
Khawaja's 47 in the first Test in Barbados is the only score from either opener above 25 in this Frank Worrell Trophy series.
The 38-year-old Khawaja fought through a difficult opening session on Saturday (Sunday AEST), as the pink Dukes ball was moving and regularly beat the bat.
But the left-hander was superbly caught behind by Shai Hope on 23, edging a ball that was angled back in at him from around the wicket by Shamar Joseph (3-33).
Konstas had also shown signs of digging in, before being lbw for 17 to Justin Greaves (3-56) after moving to an off-stump guard for this Test.
The 19-year-old at one stage faced 18 straight dot balls early, while surviving a run-out scare and edge to third slip on consecutive deliveries when on one.
Konstas threatened to find some rhythm when he hooked Alzarri Joseph's first ball for four and later punched the quick to the point boundary off the back foot.
But the teenager is now averaging just 10 for the series and Khawaja 20.6.Â
Australia have battled with the opening spot since David Warner's retirement, after Smith's aborted move up the order last year and Nathan McSweeney's three Tests last summer.
Marnus Labuschagne also opened in the World Test Championship final loss to South Africa, for scores of 17 and 22 before being dropped.
Cameron Green hit 46 before being bowled by a Jayden Seales peach, and Smith's free-flowing innings ended with an edge to a Shamar Joseph ball wide outside off.
That prompted a collapse from 3-157, as Australia lost their last seven wickets in 88 balls.
Earlier, the selectors' call to go for a fourth quick in Scott Boland ahead of Lyon marked the first since the 2013 Ashes the spinner was overlooked while fit.
Since his debut in 2011, Lyon has played 139 of Australia's 146 Tests with his only recent absence being due to a calf injury in the 2023 Ashes.
This has been a series that has generally suited the quicks, with Lyon taking nine wickets at 18.33 but only bowling 32.3 overs during the first two Tests.
Lyon has a good record in day-night Tests, but the fact this match is being played with a Dukes ball, rather than a Kookaburra, played into the decision.
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