While Wolves boss Mick McCarthy's decision to field an attacking 4-4-2 formation merely played into United's hands, United boss Sir Alex Ferguson's tactics paid off, as he made four changes to the side that lost 2-1 in Switzerland.
Phil Jones produced a confident attacking performance alongside Michael Carrick in midfield and Valencia - brought in at Ashley Young's expense - proved a constant threat on the right wing.
DID YOU KNOW?
When United were last eliminated from the Champions League group stage, in 2005, they went unbeaten in their next 10 matches in all competitions
The victory ensured United closed the gap on Premier League leaders Manchester City to two points, with Roberto Mancini's side heading to Chelsea on Monday.
The game might have taken a different course had Fletcher not sliced wide after being teed up in space on the edge of the box in the first minute.
But United soon settled into their rhythm, with Valencia enjoying plenty of space down the right and crossing for Carrick, whose diving header flew just over the bar.
Carrick then played a ball inside right-back Ronald Zubar for Rooney, whose shot from a tight angle was sharply saved by Wayne Hennessey.
Moments later, Nani cut in from the left-hand side before unleashing a powerful shot into the corner from 20 yards.
United were better than us - McCarthy
The second goal arrived in similar fashion, with Rooney this time darting across the edge of the box and smashing a shot through a crowd of players past an unsighted Hennessey.
Wolves got themselves back in the game shortly after half-time as Matt Jarvis crossed from the left for Fletcher to head his 11th goal in 16 games into the roof of the net.
The goal only served to reawaken United, who re-established their two-goal lead when Jones threaded a pass to Valencia, who crossed low for Nani to convert from six yards.
Valencia rounded off a fine afternoon's work with the assist for the fourth goal as his cross picked out Rooney to beat Hennessey with a powerful low shot on the turn.
Another marauding run from Jones almost produced a fifth goal but Hennessey did well to foil Federico Macheda at the near post.
Wolves' sixth away league defeat in eight games leaves them just three points clear of the relegation zone.
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