Bowe was carried off during Ulster's Heineken Cup home defeat against Northampton last Saturday.
In a statement released on Thursday, Ulster said: "Tommy Bowe has undergone successful surgery on his knee and is now expected to be out for approximately four months.
"The winger sustained significant lateral ligament damage to his right knee in the closing stages of Ulster's 10-9 Heineken Cup loss to Northampton."
Ireland launch their Six Nations campaign against defending champions Wales in Cardiff on February 2, before hosting England eight days later.
Bowe, who has scored 26 tries in 51 Tests, should regain full fitness ahead of the British and Irish Lions tour to Australia.
He was a key member of the 2009 Lions squad in South Africa, starting all three Tests, and would be among the leading candidates to make coach Warren Gatland's squad this time around.
For Ireland boss Declan Kidney, though, 28-year-old Bowe's absence represents another major injury blow.
Brian O'Driscoll, Paul O'Connell, Sean O'Brien and Stephen Ferris all missed the recent autumn Test schedule, which Ireland ended with an impressive victory over Argentina.
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