The Hammers made the trip to Old Trafford for the second time in four days having secured a 1-1 Premier League draw at the home of the 20-time English champions on Sunday, but this time Slaven Bilic’s side could not pick up a result.
After Zlatan Ibrahimovic’s early strike, Fletcher bagged a fairytale leveller against the club he left for east London in the summer, but Anthony Martial’s second half double and Ibrahimovic's second meant West Ham would not progress to the semi-final stage for the first time in three years.
In contrasting fashion to Sunday, it was this time the Red Devils who struck in the second minute as Ibrahimovic grabbed his second of the week against the Hammers.
Collecting a fabulous Henrikh Mkhitaryan backheel, the Swede coolly converted past the onrushing Adrian to give the hosts the lead.
And it was nearly two just five minutes later, though this time the Spaniard in goal was alert to the danger as he saved first from the goalscorer from point blank range before denying Martial a tap in.
Adrian – who was returning to the starting XI for the Cup competition – once again showed why is one of the two goalkeepers held in high esteem in east London, superbly tipping Wayne Rooney’s free-kick round the post.
But after the early pressure from Jose Mourinho’s men, West Ham began to find their feet and show composure and creativity on the ball.
It took until the 35th minute for the Hammers to have their first attempt on goal, but when it came, it was a meaningful one. Dimitri Payet, cutting in from the left, struck fiercely at David De Gea who could only spill the shot.
Up popped Fletcher – promoted to the starting lineup for the clash – to grab the equaliser against the club he left during the summer to team up with Slaven Bilic’s men.
But, like the first period, West Ham were undone quickly by the Red Devils. A throw for the visitors soon led to a second for the hosts, as Antonio Valencia’s clever flick found Mkhitaryan who put the ball on a plate for Martial to make it 2-1.
Adrian’s quality was tested again eleven minutes into the second 45, as Martial looked for a second, but the stopper could not prevent the Frenchman moments after the hour mark as he tapped home a Valencia centre.
In search of a way back into the tie, the Hammers made changes and introduced both Manuel Lanzini and Simone Zaza, though despite a period of probing and pressure from the visitors in the second period, no success came their way.
Zaza came closest to halving the deficit with seven minutes remaining on the clock after he flicked a Lanzini corner wide and Sofiane Feghouli twice missed the target in stoppage time, but the Red Devils added a fourth in stoppage time as Ibrahimovic tapped in Herrera's cross to make it 4-1 and secure their place in the semi-finals.
Manchester United: De Gea, Valencia, Jones, Rojo, Shaw (Blind 46), Carrick, Herrera, Mkhitaryan (Rashford 90), Rooney, Martial (Schweinsteiger 86), Ibrahimovic.
Subs not used: Romero, Mata, Lingard, Schneiderlin.
Goals: Ibrahimovic 2, 90+ 3, Martial 48, 62
Bookings: Rooney 53
West Ham United: Adrian, Kouyate, Reid, Ogbonna, Antonio (Lanzini 58), Obiang, Fernandes, Cresswell (Masuaku 45), Feghouli, Payet (Zaza 75), Fletcher.
Subs not used: Randolph, Nordtveit, Noble, Collins.
Goals: Fletcher 35