Paul Scholes' third goal of the season gave the Red Devils an interval lead at Upton Park before clinical second-half strikes from Darron Gibson, Antonio Valencia and Wayne Rooney finished the job in this one-sided contest.
Although two-goal Gibson had deservedly kept his place following Tuesday evening's Carling Cup quarter-final win over Tottenham Hotspur, Sir Alex Ferguson made half-a-dozen changes as Scholes, Valencia, Rooney, Patrice Evra, Darren Fletcher and the ageless Ryan Giggs came in for Nemanja Vidic, Gabriel Obertan, Danny Welbeck plus substitutes Richie de Laet, Ji-Sung Park and Dimitar Berbatov.
Crucially, Gianfranco Zola was without top-scoring, seven-goal Carlton Cole, who had injured a knee during his 17th-placed side's 5-3 win over Burnley last Saturday.
And that meant a recall for zippy Zavon Hines, who almost engineered an early Hammers opener when he crossed into the six-yard box, where last man Giggs denied the sliding Jack Collison and then Tomasz Kuszczak was forced to race from his area to head clear from the rookie England Under-21 striker.
But with West Ham lacking any focal point up front, that sadly was the extent of their first-half threat against a United side that was always in control.
Zola had also called up James Tomkins in place of Manuel Da Costa and the young defender came to his side's rescue on the half-hour mark, with a diving header that prevented the lurking Rooney from connecting with Evra's cross.
Earlier, Valencia had headed Giggs' near-post corner onto the roof of Robert Green's net, while Gibson saw his goal-bound shot cannon off Radoslav Kovac for one of the Red Devils' seven first-half corners.
Midway through the opening period, Rooney also tried his luck from 40 yards with a cheeky chip that cleared both his England team-mate Green and the crossbar.
As makeshift central defender Gary Neville (groin) hobbled away, ex-Hammer Michael Carrick was asked to slot into an equally unfamiliar centre-back slot, before the alert Green sprinted out to deny Rooney.
But just when both teams looked set to walk off goalless at the break, with less than 20 seconds of stoppage time remaining, Scholes met Danny Gabbidon's headed clearance with a rising 18-yard volley that scorched Green's right-hand glove before ripping into the net.
Hines, who had been hobbling throughout the closing stages of the first half, was replaced by Alessandro Diamanti for the restart and, after Tomkins had seen his far-post header saved by Kuszczak, the Italian substitute was much wider of the mark with an ambitious 40-yard free-kick that flew high into the stand.
On the hour-mark, though, it was game over, when Giggs collected the ball on the halfway line and played a one-two with Rooney, before moving upfield and squaring to Gibson, who sent another unstoppable 20-yarder beyond the diving Green to claim his third goal in five days.
In reply, Diamanti forced Kuszczak into his first meaningful save of the afternoon with a 25-yard free-kick that the Polish keeper clawed out from under his right-hand angle but that was merely the cue for the Manchester machine to go into overdrive.
With 20 minutes remaining the patient Rooney cleverly played in the overlapping Anderson, whose low cross into the six-yard box was tapped home by Valencia.
And within seconds of bagging his fourth goal of the season, the Ecuador international turned provider with a low centre into the danger-zone, where Rooney took his season's tally to a dozen with a simple conversion.
As many of the disconsolate West Ham fans amongst the sold-out crowd of 34,980 trudged away in the East End rain, the physically sick Green joined them as substitute keeper Peter Kurucz entered the fray for an unenviable debut.
But the Hungarian fortunately found himself untroubled against a wound-down United side, that could even afford the luxury of finishing with ten men after the injured Wes Brown added to Ferguson's defensive worries ahead of Tuesday night's Champions League trip to VfB Wolfsburg.