Horwill had been playing through the pain barrier
James Horwill has been ruled out of Australia's tour of Hong Kong and Europe in November because of injury.
The Queensland Reds lock is set to undergo foot surgery and could be sidelined for up to six months.
Horwill has played with the injury since Australia's 16-9 win over South Africa in Perth in July.
The 23-year-old was one of only four Wallabies to start in all nine Tests this year and was the team's equal leading try-scorer with four.
Australia coach Robbie Deans said: "It's disappointing news, but playing on wasn't an option.
"The injury had been given plenty of opportunity to settle but hasn't."
Australia have named four uncapped players in a strong 33-man squad.
Teenage back James O'Connor, flanker David Pocock, fly-half Quade Cooper and prop Sekope Kepu are all included.
Berrick Barnes, Wycliff Palu and Luke Burgess return after missing the end of the Tri-Nations while Lote Tuqiri is expected to recover from a knee injury.
The Wallabies will play five Tests on tour, taking on England on 15 November before playing Wales two weeks later.
The two-time world champions will also face rivals New Zealand in Hong Kong on 1 November in the first ever off-shore Bledisloe Cup match.
Western Force utility back O'Connor is the biggest surprise in Deans' squad, but the former All Blacks coach believes the 18-year-old has a bright future ahead of him.
"We believe he is good to go in terms of starting his development as an international player," said Deans.
"He has been included primarily to learn his trade, but we believe he has a lot to offer now, and will only build on that with the experience he will gain in our environment during the next two months."
Should O'Connor earn a starting place, he would become Australia's second youngest Test player ever after winger Brian Ford, who made his debut in 1957.
Centre Stirling Mortlock has been retained as captain.
Australia squad to tour Hong Kong and Europe:
Backs: Adam Ashley-Cooper, Berrick Barnes, Luke Burgess, Quade Cooper, Sam Cordingley, Ryan Cross, Matt Giteau, Peter Hynes, Digby Ioane, Drew Mitchell, Stirling Mortlock (captain), James O'Connor, Brett Sheehan, Timana Tahu, Lote Tuqiri, Lachlan Turner.
Forwards: Ben Alexander, Al Baxter, Richard Brown, Mark Chisholm, Matt Dunning, Adam Freier, Sekope Kepu, Hugh McMeniman, Stephen Moore, Dean Mumm, Wycliff Palu, David Pocock, Tatafu Polota-Nau, Benn Robinson, Nathan Sharpe, George Smith, Phil Waugh.
1 November: New Zealand, Hong Kong
8 November: Italy, Padova
15 November: England, London
22 November: France, Paris
29 November: Wales, Cardiff
3 December: Barbarians, London