After his latest miss, Rooney was passed over in favour of Ryan Giggs to take United's third-minute spot-kick. And, 20 years and three days after his first FA Cup goal, Giggs scored his 12th.
Rooney did not come alive until after the restart but once he had brutally fired home his 10th goal of the season, he quickly set up strike partner Javier Hernandez for the Mexican's 13th. Hernandez bagged another before Aaron Hughes' consolation, ensuring Robin van Persie could remain on the bench throughout.
Giggs strode straight into the area once Mark Clattenburg had spotted Aaron Hughes handling Rooney's corner. In more than two decades, the only times Giggs had missed in such situations were in shoot-outs, and though Mark Schwarzer got a hand to this one, the Australian was unable to keep it out.
The hosts should have had another when Giggs' pass for Patrice Evra rolled off Damien Duff's arm. Inexplicably, Clattenburg ruled this intervention accidental and Fulham's escape was complete when Schwarzer turned Rooney's shot onto the crossbar as the hosts pressed at the corner.
Sascha Riether drilled a long-range effort just wide, just the reminder United needed that their place in the last 16 was not assured, and which they rectified within five minutes of the restart.
Anderson deserved immense credit for his brilliant through-ball. But the goal clearly meant something to Rooney, who turned inside Hughes then sent a ferocious shot flying past Schwarzer.
On United's next attack, Nani's trickery put Fulham's defence on the back foot before Rooney's cross ended up with Hernandez, who lashed home a close-range volley.
And midway through the half Hernandez had another, charging onto Giggs' pass before his shot deflected off Hughes and gave Schwarzer no chance. It was the Mexican's fifth goal in six games, underlining the fact United are not quite as reliant on Van Persie as some people seem to think.
Not that everything went to plan for the hosts. David De Gea was not culpable for Fulham's consolation but the ease with which Hughes rose at the near-post to steer home Giorgos Karagounis' corner was alarming for a side with only seven clean sheets all season.
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