The Red Devils thrashed the La Liga side 4-1 at Old Trafford, and barring a massive shock, Erik ten Hag's men should breeze into the quarter-finals.
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The Red Devils have already lifted the Carabao Cup this season and will see the Europa League as another chance for silverware.
But their domestic form has slightly dipped after a 7-0 thrashing by Liverpool and a goalless draw with Southampton.
Meanwhile, Manuel Pellegrini's men need to overhaul a three-goal deficit just to draw level with United, so a comeback appears unlikely.
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Betis vs Man United: talkSPORT coverage
This Europa League round of 16 second leg clash is scheduled for Thursday, March 16.
Kick-off at the Benito Villamarín Stadium is set for 5:45pm UK time.
talkSPORT 2 will have live commentary from Spain courtesy of Jim Proudfoot and former Republic of Ireland midfielder Matt Holland.
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To tune in to talkSPORT or talkSPORT 2 through the website, click HERE for the live stream.
You can also listen via the talkSPORT app, on DAB digital radio, through your smart speaker and on 1089 or 1053 AM.
Betis vs Man United: Team news
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The Red Devils are without Antony due to illness and he hasn't made the trip to Spain.
Anthony Martial has also been left in Manchester, but Casemiro will be involved before he starts his four-game domestic ban for a second red card of the season against Southampton.
Alejandro Garnacho, Christian Eriksen and Donny van de Beek are all injured, but Marcel Sabitzer and Victor Lindelof are back.
Meanwhile, the hosts are without Luiz Felipe due to a hamstring injury - while 41-year-old Joaquin could start.
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Betis vs Man United: What has been said?
Betis and former Manchester City manager Pellegrini: "We must try from the first minute.
"First to win the game, after that to try to score the goals that we need to qualify. And if not, to play a good game and win here at home.
"So, believing in my team, believing in our fans and we try, all together, to turn the score."
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Betis vs Man United: Match facts
This is Real Betis' first home European game against an English side since November 2005, when they beat Chelsea 1-0 in the UEFA Champions League group stages.
Including this game, five of Manchester United's last seven away European games have been in Spain - they haven't lost any of their last four (W2 D2), beating Real Sociedad and drawing at Barcelona this season alone.
Real Betis have only progressed from one of their previous six major European ties when they have lost the first leg, overcoming a 1-0 first leg loss to Vejle BK in the first round of the UEFA Cup in 1998-99 to win 5-1 in the second leg.
Of all teams to win by a 3+ goal margin in the first leg of a UEFA Europa League knockout tie (2009-10 onwards), only one has ever been eliminated: Basel vs Valencia in the 2013-14 quarter-final (won 3-0 first leg, lost 5-0 second leg).
Marcus Rashford has scored 24 goals in major European competition for Manchester United and could become only the sixth player to score 25 such goals for the Red Devils and, aged 25 years and 136 days on the day of this game, the youngest player to reach 25 major European goals for the club. He would also be the youngest Englishman to score 25 goals in major European competitions in history.