Zamora, who made his England debut last month, was injured during Saturday's 2-1 victory over Wolves and underwent surgery this week.
Hughes said: "Bobby's had his operation. He will now be in bed with his leg elevated for two weeks. The operation showed ligament damage so we're probably now looking at five months.
"We want to help Bobby get back quickly and there are no concerns over his ability to get back to the level he was before he got injured."
Fulham are also without long-term absentee Andy Johnson, which means new signing Moussa Dembele will be expected to lead the attack.