Erik ten Hag's side responded to the humiliating 7-0 defeat against Liverpool on Sunday in an encouraging way by thrashing the Spanish side at Old Trafford.
Rashford got United off to an ideal start with a thumping finish early in the game, setting the tone for what was to come from a reinvigorated attack.
Betis levelled against the run of play with a controversial goal from former Leicester forward Ayoze Perez after team-mate Juanmi appeared to control the ball with his arm in the build-up.
Antony restored United's lead with a trademark strike into the far top corner after cutting in from the right before Bruno Fernandes headed in the third.
Wout Weghorst then scored a much-needed goal on a personal level to put the Red Devils in a really strong position heading into next week's second leg in Seville.
GOAL rates Manchester United's players from a much happier evening at Old Trafford.