The Aviva Premiership club announced on Tuesday that 29-year-old O'Leary has undergone surgery to his lower back for what they describe as a "degenerative pre-existing injury" that has deteriorated this term.
In a statement, Irish said: "Tomas has been unavailable for selection since his last appearance for London Irish against Harlequins at Madejski Stadium on October 28. He now faces a four to six months lay-off."
O'Leary, who has won 24 caps for Ireland, joined London Irish on a three-year contract at the start of this season.
He previously played for Munster and was selected to tour South Africa with the 2009 British and Irish Lions.
But he suffered a broken ankle while playing for Munster against the Scarlets just a month before the three-Test trip, and was then ruled out of the tour.