Horne has suffered a hamstring tear just a week ahead of the Waratahs Super Rugby campaign and joins a concerning casualty list.
Drew Mitchell (calf strain), Berrick Barnes (knee) and Bernard Foley (ankle) are all currently sidelined with the latter duo rated only as 50-50 for the season opener against Queensland Reds on February 23.
The injuries are the last thing the Wallabies' stars need as they begin their preparations for the arrival of the Lions in June.
Michael Cheika also has concerns over wing Peter Betham who is battling an ankle injury.
The situation opens the door for 22-year-old newcomer Ben Volavola to stake a claim to the Waratahs' fly-half jersey.
"They're (injuries) a bit troubling because they are all around that same position that 10, 12, 13," said Cheika.
"But sometimes the circumstances push something to the surface and Ben Volavola is going to get a good chance to take the lead in the race for that 10 jersey.
"There's a few options at 12 obviously. Tom Carter, Michael Hodge are options.
"It just depends on the mix. At this stage I'm not too worried about next week (Reds). We'll just see who plays well in Thursday's game against the Crusaders and try and pick a team from there."
Volavola is likely to go head-to-head with New Zealand superstar Dan Carter in the franchise's final trial encounter.
But following a string of impressive performances Cheika has backed the rookie to shine.
"He'll probably be so excited about going out to match up against a guy like Dan Carter," added Cheika.
"And it's up to the rest of the of the team to make sure he can challenge one of the best players in the world in his own position."