Rooney, Ronaldo and Carlos Tevez were an impressive attacking force, backed up by the talented Nani.
Australian international forward Mark Viduka was again omitted by Newcastle, who paired Michael Owen with former Manchester player Alan Smith, yet to score a senior goal for Newcastle in 27 appearances this season.
Much of the euphoria surrounding Kevin Keegan's return as manager at Newcastle has faded, after a return of two points from a possible 15 and growing concerns about a relegation battle.
In the 25th minute, Ronaldo tricked his way past fullback Habib Beye and crossed to the far post where Rooney volleyed past Shay Given.
When midfielder Joey Barton lost possession to Rooney a neat pass set up Michael Carrick, who played in Ronaldo and the Portuguese fired past Given. The keeper was replaced by Steve Harper for the second session but the sub fared no better.
Eleven minutes after the restart Harper was left floundering as Ronaldo darted round him to score the third goal.
Sir Alex Ferguson then withdrew Ronaldo and the injured Nemanja Vidic with the win assured and Newcastle scored 11 minutes from time.
Andy Carroll headed James Milner's corner into the path of Abdoulaye Faye and the Senegal international netted from close in
Less than two minutes later Smith cleared a corner straight into the path of Rooney who fired in from 22 yards. Louis Saha completed the rout in the final minute.
Fernando Torres scored a hat-trick as Liverpool beat Middlesbrough 3-2 at Anfield and lifted Rafael Benitez' side back into the top four.
It was Boro's first defeat since New Year's day and was made worse when striker Jeremie Aliadiere was sent off late in the game after a clash with Javier Mascherano.
Fulham were pushed closer to the drop after a 1-0 home defeat by West Ham while Wigan gave their surival chances a huge boost by beating bottom side Derby 2-0.
Nolberto Solano claimed the points for West Ham with an 87th-minute strike at Fulham, who had Denmark defender Leon Andreasen sent off when he picked up a second yellow card for his protests to the referee about the goal.
Late goals from Paul Scharner and Antonio Valencia lifted Wigan four points clear of the relegation zone.
Sunderland are in an identical position after succumbing to a 1-0 defeat at Portsmouth, for whom Jermain Defoe slotted in a penalty with just over 20 minutes left.