Irvine's club, Bundesliga 2 outfit St Pauli, confirmed in the early hours of Friday morning (AEST) that the 30-year-old had suffered an anterior talofibular ligament sprain during last week's 2-2 friendly draw with Mexico in Dallas.
While Socceroos coach Graham Arnold initially believed Irvine had only rolled his ankle, Irvine's German club said that after further assessment the midfielder would be "sidelined until further notice".
The injury deprives Irvine of the chance to face England at Wembley Stadium in October.
He will also miss the friendly against New Zealand in Brentford during the same international window and faces a battle to get fit in time for November's World Cup qualifiers.
Socceroos staff will monitor Irvine's progress on a weekly basis and won't put a line through the availability of one of Australia's most-experienced players until nearer the time.
Australia will host the winner of a play-off between Bangladesh and the Maldives and will travel away to face Palestine.
Should Irvine be absent for the games - which the Socceroos will be expected to win comfortably - it puts Australia's midfield in a further state of flux ahead of January's Asian Cup in Qatar.
Aaron Mooy's retirement earlier this year has left a chasm in the heart of the Australian side and the absence of 55-cap veteran Irvine only adds to that.
Of the six remaining midfielders called up by Arnold for the Mexico friendly, only Riley McGree has 10 or more caps.
Irvine's absence potentially opens the door for others to state their case for the Asian Cup campaign.
Massimo Luongo could be in line to return from the international wilderness after enjoying a sparkling start to the English season with Championship outfit Ipswich Town, while rising youngster Alex Robertson was left out of the Mexico squad to focus on club commitments.
