First-half goals from James McCarthy and John Stones put hosts Everton in control at Goodison Park and substitute Kevin Mirallas sealed victory on the counter-attack late on.
Fourth-placed United enjoyed plenty of possession but lacked any cutting edge with striker Radamel Falcao's frustration complete when he had consolation goal disallowed for offside.
Defeat, following last week's reverse against Chelsea, leaves United still a comfortable seven points above fifth-placed Liverpoool although that gap could be sliced to four if Liverpool win their game in hand at Hull City on Tuesday.
It proved a frustrating afternoon for former Everton players Wayne Rooney and Marouane Fellaini.
Fellaini wasted a great chance to equalise and was booked for hacking down Seamus Coleman shortly afterwards.
Everton increaesd their lead with a powerful Stones header from a corner that Ashley Young, positioned on the goal line, could not keep out of the net.
Everton completed their biggest win over United for 23 years in the 84th minute when Mirallas charged through from deep to finish cooly with United's defence expecting an offside flag to be raised against Romelu Lukaku.