The 28-year-old national team captain suffered an ankle injury in United's shock 2-0 defeat against Fulham on Saturday and will now miss the trip to Dublin on March 28 and the home tie against the Cypriots that follows.
His injury comes as a blow to Bulgaria coach Stanimir Stoilov's hopes, with Manchester City's Martin Petrov and Leicester City's Alexandar Tunchev already laid low by injuries.
Bulgarian national team doctor Mihail Iliev said: "There's no chance Berbatov of playing against Ireland and Cyprus.
"I've talked to Manchester United's medical staff and they informed me that he'll need to rest in the next two weeks and his foot will be immovable during that period."
Stoilov is yet to announce Berbatov's replacement, but with Bulgaria currently sitting third in Group eight with three points from three matches they face a real challenge at Croke Park.
Italy top the group standings with 10 points from four games followed by Ireland, who trail only on goal difference, so the visitors cannot afford to lose if they are to keep their hopes of making the 2010 finals alive.