The hosts piled on the pressure after going behind, but even the introduction of Bruno Fernandes and Mason Greenwood off the bench was not enough as the Hammers held on to secure an unlikely cup victory.
David Moyes continues to create history at West Ham, and he led the club to their first win at Old Trafford since May 2007. He also managed his first victory against Manchester United since leaving the club in 2014.
Story of the match
There were wholesale changes to both sides following Manchester United's 2-1 victory against the Hammers on Sunday, with West Ham forward Jarrod Bowen the only man to keep his place and start both games.
The first chance of the game fell to the visitors after Andriy Yarmolenko found space in behind and picked out a teammate on the edge of the box, however the aforementioned Bowen dragged his effort wide of Dean Henderson's goal.
Moyes' men looked the more lively early on, and they took a deserved lead just before the 10-minute mark through Manuel Lanzini, the Argentine converting well inside the area following good work from Ryan Fredericks down the right-hand side.
Fredericks was unable to shake off an injury sustained in the build-up, and he was replaced by Vladimir Coufal minutes later.
The hosts rattled the bar shortly after West Ham's opener as they sought to repeat the weekend's events and find an immediate equaliser, Juan Mata going close after the Hammers debutant between the sticks failed to deal with a corner.
West Ham's early goal seemed to wake up the Reds, and the next opportunity was presented to Anthony Martial, the Frenchman was unable to find the far post from close range, however.
Alongside David De Dea, Jesse Lingard stole the show at the London Stadium on the weekend, and he forced a good save from Areola as he looked to repeat his heroics, Solskjaer's men piling the pressure on the away side.
Half-chances for Martial and Donny Van De Beek followed before the interval, but the men wearing Blue and White stripes did enough to hold on, partly thanks to animated assistant Stuart Pearce whose instructions to remain organised could be heard around the ground.
West Ham United (@WestHam) September 22, 2021
The Red Devils resumed their dominance in possession right from the restart as the visitors continued to maintain their low-block, waiting for an opportunity to break on the counter.
Jadon Sancho was quiet during the first 45, but he had the first shot at goal after the break as he searched for his first United goal, the former Dortmund man firing over after racing on to Mata's lofted pass.
The tricky winger showed desire to get involved, and drew a booking from Mark Noble after showing good skill to turn on the halfway line.
United continued to throw bodies forward with the full-backs pushing high up, and defender Diogo Dalot was the next to try his luck as his shot across goal went wide.
Chances for West Ham were limited, but Yarmolenko was not far away from doubling his side's advantage with a thunderous left-footed effort from distance on 60 minutes. With an hour gone, and still trailing, United looked to the bench to introduce one of their regular starters...
Manchester United (@ManUtd) September 22, 2021
Greenwood almost made an immediate impact after just 40 seconds on the pitch, showing great awareness to latch on to a ball over the top, but Areola held his position and saved well.
With 20 minutes to go, and the hosts side struggling to create clear-cut chances, the Reds made a double switch. Bruno Fernandes was called upon to inject some creativity, and youngster Elanga an alternative option on the left...
Manchester United (@ManUtd) September 22, 2021
Fernandes made a difference, and he almost made it 1-1 with an ambitious hit from distance on 78 minutes, the Hammers defenders breathing a collective sigh of relief as the ball whistled wide.
Martial's poor form in front of goal continued as he failed to poke home following a corner, and West Ham could have been through on goal as they raced up the other end if it wasn't for a last-ditch Bruno tackle.
Yarmolenko should have sealed things when he rounded the keeper with 5 minutes to go, but he was denied by the post.
Then there was almost a fairytale ending as Mark Noble had a one-on-one opportunity to atone for his penalty miss in Sunday's loss, but he couldn't convert and Man United were kept alive.
West Ham kept going forwards as they aimed to kill off the game, and Pablo Fornals was the next player to miss as the closing minutes dragged out, the Spaniard blazing over from the edge of the area.
The home team won a corner in the 92nd minute to which Henderson was sent forwards, however the set-piece came to nothing and West Ham held on for a famous victory.
A cup upset, and the Hammers into the next round of the Carabao.
Look at that smile! 😁 pic.twitter.com/BQJ2y8Uvev— West Ham United (@WestHam) September 22, 2021