Manuel Pellegrini's side were put to the sword 4-1 by the Red Devils in last week's first leg - the perfect response to their Liverpool embarrassment for Erik ten Hag's XI.
Match preview
While Ayoze Perez's well-taken strike upon his return to English soil gave Betis a glimmer of hope at Old Trafford, Pellegrini's Manchester comeback was ultimately a miserable affair for the former Manchester City manager, whose men succumbed to a second-half assault.
Perez's equaliser followed a thunderous opening goal from Marcus Rashford after just six minutes, and Ten Hag's half-time team talk went down a treat, as Antony, Bruno Fernandes and Wout Weghorst all contributed to the rout to leave Betis on the brink of elimination.
Defeat at the Theatre of Dreams was sandwiched in between a pair of La Liga stalemates with Real Madrid and Villarreal for Los Verdiblancos, who were pegged back against the latter by Yeremy in a 1-1 draw at the weekend, leaving them fifth in the table but only three points behind Real Sociedad amid their counterparts' sticky patch.
Yet to progress beyond the last 16 of the Europa League in its current format, Betis only have one win from their last seven home matches to shout about ahead of the visit of Man United, but following in the footsteps of compatriots Valencia would serve them very well indeed here.
During the 2013-14 Europa League quarter-finals, Valencia lost 3-0 to Basel in the first leg before storming to a 5-0 second-leg success - no other team has recovered from a three-goal deficit to progress from a knockout tie in Europe's secondary competition.
Going through a world of emotions within the space of a week, Man United fans have experienced the true meaning of a tumultuous period, which continued with a high-octane goalless draw against Southampton in which goalkeepers and the woodwork stole the show.
Casemiro cut an inconsolable figure as he was sent off for a dangerous challenge on Carlos Alcaraz in the first half, and no fewer than 28 shots were fired across the 90 minutes at Old Trafford, but the net would not ripple once as the two sides played out a gripping stalemate.
Any fleeting hopes of Ten Hag's side knocking on the door of the top two in the Premier League table can surely be considered long gone, but further knockout success is still very much on the cards, and Man United have never been eliminated from the last 16 of the Europa League when winning the first leg.
Winning just two of their last six away games does not bode all that well for Ten Hag's team, but Man United have gone unbeaten in their last four trips to Spain and simply need to avoid a calamitous collapse to put their name in the pot for the quarter-finals.
Real Betis Europa League form:
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Real Betis form (all competitions):
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Manchester United Europa League form:
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Manchester United form (all competitions):
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Team News
Injury was added to insult for Betis at Old Trafford, as centre-back Luiz Felipe completed the full 90 but left the field with hamstring discomfort, and he could now be missing until after the international break - Victor Ruiz should deputise.
Felipe will be one of three absences for Thursday's game alongside long-term knee victim Nabil Fekir, who will not play again this season, and Juan Cruz, but William Carvalho is back from a La Liga bam.
A sixth Europa League start of the season came the way of Joaquin in the first leg, but Sergio Canales's return to full fitness could force his 41-year-old compatriot out of the XI here.
Meanwhile, Casemiro's four-game domestic ban will not impact his participation this week, but Ten Hag must still factor in a plethora of injury concerns, with Donny van de Beek and Christian Eriksen already known to be missing out.
Alejandro Garnacho also left Old Trafford on crutches at the weekend, and there are fears that the teenager's ankle problem is worse than first feared, while Victor Lindelof (illness) and Marcel Sabitzer (knock) will both need assessing too.
On a brighter note, Anthony Martial is building up his fitness in team training and could be considered for some minutes in Spain, but Ten Hag is still being cautious with the Frenchman and will surely only name him on the bench at best.
Real Betis possible starting lineup:
Bravo; Sabaly, Pezzella, Ruiz, Miranda; Carvalho, Rodriguez; Canales, Perez, Juanmi; Iglesias
Manchester United possible starting lineup:
De Gea; Wan-Bissaka, Varane, Maguire, Malacia; Casemiro, Fred; Antony, Fernandes, Sancho; Rashford
We say: Real Betis 1-2 Manchester United (Man United win 6-2 on aggregate)
With a comfortable three-goal cushion to protect and no reason to go gung-ho on the night, expect a much more low-key second leg from Man United, whose lengthening injury list could see Ten Hag avoid taking many risks on Spanish soil.