Zebo is expected to be sidelined for 10 weeks, leaving him with next to time to prove his fitness before Warren Gatland names his Lions touring squad at the end of April.
"Simon Zebo will miss the rest of the championship after breaking a bone in his foot in the opening minutes of the game against England in Dublin yesterday," read a statement on the Munster website.
"Initial reports suggest that he will also miss the Heineken Cup quarter final clash with Harlequins at The Stoop in early April."
Despite only making his international debut on the summer trip to New Zealand, Zebo was being heavily tipped to press for a Lions call up after a series of impressive performances for both Munster and Ireland over recent weeks.
A hat-trick in the televised Heineken Cup victory over Racing Metro was followed by a fine display against Wales last week, with the 22-year-old claiming Ireland's first score and then setting up Cian Healy for the second with a sublime piece of individual skill.
Zebo is set to have surgery some time today, with an update expected later this week.
His absence could see Ulster's Andrew Trimble win an Ireland recall, although 2009 Lions Keith Earls and Luke Fitzgerald or Leinster utility back Fergus McFadden will also come into the reckoning.
Tommy Bowe - who played in all three Tests for the Lions in South Africa four years ago - is still unavailable following knee surgery and won't return in time to play any part in the remainder of the tournament.
The former Ospreys star is expected to feature for Ulster in their end-of-season run-in, however, and his experience could still see him win a spot on a second successive Lions tour this summer.