The 23-year-old went down after a challenge by Sky Blues attacker Richie Garcia midway through the second half just minutes after coming on as a substitute.
While he tried to play on, Mebrahtu was forced off soon after with initial reports he has ruptured his ACL and will require a full knee reconstruction.
Signed to the club only a couple of months ago as a reinforcement for the club's Asian Champions League campaign, the former Melbourne Heart striker will have scans on Sunday to learn his fate.
"It's very unfortunate for the boy. He's devastated," Wanderers boss Tony Popovic said.
"It sums up our night really. The boy comes on makes his debut and his first touch it looks like it an ACL.
"He's doing it pretty tough in the change room at the moment."
Mebrahtu's injury compounded a sorry night for the Wanderers, who slumped to their first derby defeat in five after losing 3-1 at Allianz Stadium.
Popovic's troops looked on track for a third straight win on Sydney's home turf when Shinjo Ono opened the scoring early in the second half.
But a penalty miss from former Sky Blue Mark Bridge two minutes later turned the match, with Sydney finishing over the top of Wanderers, who have now lost three games on the trot.
Again they were undone by defensive errors, with Sydney's second goal from Richard Garcia a calamitous mistake from skipper Michael Beauchamp.
"It's a frustrating night in the end. We lost a game we never should have lost," Popovic lamented.
"We made mistakes again and got punished. We're going through a little period now where every mistake we're going through we're being punished for it.
"As a whole we defended well. How many chances did Sydney create in general play? There were no chances created.
"We had a chance to go two up with the penalty but they were mistakes that got them in the game. They took advantage of it and we lose."
Popovic insists he hasn't given up hope of catching Brisbane for the Premiers' Plate, despite being seven points behind the Roar – who have a game in hand – with just five rounds left to play.
Western Sydney head to China on Sunday for a midweek Champions League clash with Guizhou Renhe before coming home on Friday ahead of their home clash with Adelaide 24 hours later.
