The Portuguese forward, last season's European Golden Boot winner with 40 league goals, opened the scoring from Gonzalo Higuain's layoff in the 23rd minute, to take his total in all competitions to 38.
Sami Khedira doubled the lead after playing a one-two with his German international team-mate Mesut Ozil in the 38th minute and Higuain buried a third just after the re-start.
Jose Mourinho's team moved a step closer towards their first league title in four years as they climbed to 67 points with 13 left to play.
"We're very pleased," Argentina international Higuain told Spanish television.
"There's still a long way to go so it was important for us to maintain our points advantage."
Sofiane Feghouli earned Valencia a 1-0 victory at Granada, his side's first road win in La Liga since November, to keep them third in the standings with 43 points.
Home goalkeeper Julio Cesar made a hash of parrying the Frenchman's tame shot in the 32nd minute in a scrappy match littered with yellow cards.
Valencia's second league win of 2012 strengthened their hold on third place ahead of Athletic Bilbao in fourth with 37.
Manchester United's opponents in the Europa League next week moved into the Champions League places with a 2-0 home win over Real Sociedad in the Basque derby.
