The No.15 will return home and consult specialists after scans confirmed an anterior cruciate ligament injury suffered early in Saturday's 30-22 loss to South Africa in Cape Town.
Wright, a star of last week's triumph in Johannesburg, has emerged as one of the world's premier fullbacks to power Joe Schmidt's improved Wallabies.
He'll now join a crowded injury list ahead of a crunch double against Argentina in Townsville and Sydney, before the Bledisloe Cup.
Assuming Wright requires surgery, he'll miss the five-game tour of Japan and Europe later this year and, ahead of the 2027 home World Cup, the next Super Rugby Pacific season with the ACT Brumbies.
Scrumhalf Nic White and centre Joseph-Aukuso Suaalii were both concussed in the first half while prop Taniela Tupou dislocated a finger shortly before the break.
Skipper Harry Wilson (knee), James Slipper (concussion) and Dylan Pietsch (broken jaw) were all injured in the Rugby Championship opener in Johannesburg.
Flyhalf Ben Donaldson (groin) was also ruled out before that game while Harry Potter, Matt Faessler, Allan Alaalatoa, Tom Lynagh and Jake Gordon - the latter pair the starting halves against the British and Irish Lions - didn't make the trip.
Wright's left knee seemed to buckle as he went to change direction to pick up a loose ball.
The 28-year-old limped to the bench and cut a devastated figure as he slumped to the turf and put his head in his hands to contemplate his misfortune.
The Wallabies' campaign continues against Argentina on September 6.
Australia will face the South Americans again on home soil a week later, before taking on arch rivals New Zealand in Auckland on September 27, then in Perth on October 4.
Argentina's shock 29-23 victory over the All Blacks in Buenos Aries means all four teams in the Rugby Championship have a 1-1 record in what is shaping up to be a thrilling race for the crown.
"After today and even losing three guys last week, the attritional nature of the tour is going to make it a little bit more difficult coming up against Argentina," Schmidt said post-game.
"Because I do have massive respect for not just their team, but their coaching staff as well.
"(Coach) Felipe Contepomi I know well and have a lot of time for. That's something once we land back in Australia we'll work out.
"But our strength and depth is going to be tested. So the guys who are experienced, they're going to have to get around the new guys who come in and we're going to have to calibrate those guys as quickly as possible, assimilate them into the group and try to kick on against Argentina in two weeks' time."
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