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.
Kaka set up the third, bagged the fourth with a run and shot off the post in the 66th, and pulled back for Higuain to hammer the fifth high into the net in the 78th.
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."
Champions Barcelona survived a 46th-minute red card for Gerard Pique to beat lowly Sporting Gijon 3-1 at home to move on to 57 points on Saturday.
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.
Markel Susaeta scored in each half, the second a superb free-kick struck into the top corner 10 minutes from time.
The visitors from San Sebastian were unlucky not to level at the beginning of the second half when a Carlos Vela shot appeared to cross the line before Gorka Iraizoz got to the ball.
Sixth-placed Levante with 35 points can reclaim fourth place with a win at home to Real Betis on Monday.
Basement side Real Zaragoza kept alive their hopes of avoiding the drop with a 2-1 win against Villarreal, thanks to goals from Luis Garcia and Abraham Minero in the last five minutes.
The cash-strapped club, who are in administration, earned their first home win since October and have 18 points, nine from safety.
