United had lost 2-1 at the same stage last season before rallying to thrash the Italian side 7-1 in the second leg at Old Trafford.
There was to be no repeat of that romp at the Stadio Olimpico as the game started off in cagey fashion before United broke loose and in the end could have secured victory by a greater margin.
Roma were without inspirational captain and playmaker Francesco Totti after he picked up a thigh injury while on Serie A duty at the weekend.
However, they created the early running and Christian Panucci should have done better than to head a corner over from close range in the 16th minute after rising above Michael Carrick.
United though were not so profligate and, after playing their way into the game, broke the deadlock with their first real opportunity.
Paul Scholes was the architect as he patiently stood the ball up on the penalty spot after being played into space in the penalty area and the onrushing Ronaldo bulletted a downward 39th minute header into the back of the net.
The Portuguese winger had been subdued up that point but his 36th goal of the season in all competitions was a massive blow for Roma who had looked the more likely to score.
The home side started the second period on the front foot and the lively Mirko Vucinic turned in the box and teed up Max Tonetto, but he drilled a powerful rising shot wide from an angled position when he should have tested Edwin Van der Sar.
Panucci then wasted the home side's best chance when he took advantage of rare hesitancy in the United defence to ghost into the box unmarked only to side-foot a volley from a long throw over the crossbar.
Van der Sar then preserved the narrow advantage as his stuck out a left hand to claw away Vucinic's flicked header from a corner as Roma built up a head of steam.
But their failure to break through was compounded when Rooney capitalised on a goalkeeping error to stab the ball home in the 66th minute to double the advantage.
Ji-Sung Park headed a deep cross back into the six-yard box and, when Doni fumbles the ball, the England striker reacted first to nudge it over the line from three yards.
Ronaldo then forced Doni to push his low drive onto the upright, while Carrick sliced a low shot wide of the mark when picked out by Rooney on the edge of the penalty area in the 71st minute.
There was still time for Rooney to mis-hit a curling shot wide of the far post as United broke with intent in the final ten minutes, before Ronaldo lashed a difficult volley from an acute angle high and wide in the dying seconds.
However despite their late misses, United fully deserved their two-goal lead which moves them to within touching distance of the last four and a semi-final meeting with either Barcelona or Schalke.