Hojlund marked his 21st birthday by scoring in a fourth league game in succession to put the home side ahead at half-time despite a decent Hammers showing.
Garnacho's deflected effort soon after the restart, however, effectively killed the game off, before the same player added a clincher late on, with the Hammers suffering their first league defeat since the 5-0 loss at Fulham in early December.
Here's how David Moyes's side rated at Old Trafford...
Decent parry early on to keep out Bruno Fernandes's dipping strike before coming off at half-time as a precaution.
Returned from suspension and kept Marcus Rashford fairly quiet.
Just doesn't quite look at his best at the moment, with injuries perhaps taking their toll. Steered a decent chance wide late on, but denied Fernandes a third with a sharp tackle.
Back from the Africa Cup of Nations but got caught square on as Hojlund struck and then unlucky to see Garnacho's first strike deflect off him and in.
Terrible decision to shoot when cut-back might have seen West Ham level after the break. Garnacho had scored at the other end within seconds.
Brilliant pass created chance for Bowen to pull one back. A big presence in the middle of the park.
Early header almost led to opener via deflection off Alvarez but Andre Onana save was smart. Booked.
James Ward-Prowse 6
Lost out to Casemiro in build-up to opener. Form has dipped badly in recent weeks.
Ben Johnson 6
Surprisingly deployed on the right wing but gave a decent account, including a couple of well-hit efforts from range.
Jarrod Bowen 6
Needed to be more decisive when put through by Alvarez, though Diogo Dalot's block was superb. Looks the player missing Paqueta most.
Several fine driving runs up the centre of the park but faded after the break.
Lukasz FabiaÅski (Areola 46') 6
Called upon at half-time but had no chance with Garnacho strike after deflection.
Maxwel Cornet (Soucek 72') 5
Kalvin Phillips (Coufal 72') 4
Is having a dreadful start to his West Ham career, losing ball in build-up to Garnacho clincher.
Unused: Ogbonna, Cresswell, Mavropanos, Scarles, Mubama, Ings