The Red Devils progressed past Barcelona 4-3 on aggregate in the knockout round playoffs, while Manuel Pellegrini's crop beat Roma, HJK Helsinki and Ludogorets to top spot in Group C.
Match preview
The highs of ending a six-year trophy drought and eliminating Barcelona from European competition paled into insignificance for Man United on Sunday afternoon, as a mortified Erik ten Hag witnessed the Red Devils suffer their worst defeat in Premier League history at the hands of a merciless Liverpool.
Cody Gakpo, Mohamed Salah and Darwin Nunez all bagged braces alongside a Roberto Firmino effort in the true meaning of a demolition job, bringing an end to the Red Devils' 11-game unbeaten run while sparking euphoria and exasperation from pundits, fans and players in equal measure.
With a 14-point gap to make up to leaders Arsenal - who have played a game more - some have already eliminated third-placed Man United from the Premier League title race, but their podium spot is safe for the time being as they seek an immediate response in continental action.
A second-placed finish to Real Sociedad in the group stage forced Man United to do it the hard way, but a richly-deserved 2-1 second-leg win over Barcelona propelled the Red Devils into the last 16 at the Catalans' expense, and not since March 2012 have the hosts lost the first leg of a European knockout tie at home.
Prior to being destroyed by Liverpool, Man United had scored at least twice in 12 successive games in all competitions - their multiple-goal run at Old Trafford stands at an even better 14 games - and Ten Hag's side can get straight back into the fans' good books with a 20th unbeaten match in a row at the Theatre of Dreams here.
A familiar face returns to the northwest in the opposition dugout, as ex-Manchester City boss Manuel Pellegrini - who can expect a hostile welcome when he emerges from the Old Trafford tunnel - travels back to the UK with his side hitting form at the right time.
Following a trio of successive victories against Almeria, Real Valladolid and Elche - during which Betis scored eight goals while shipping five themselves - Pellegrini's side held reigning Spanish and European champions Real Madrid to a goalless draw at the weekend, keeping Los Blancos at bay despite having just 38% possession.
A near-perfect Europa League group stage for Los Verdiblancos saw them win five games and draw one in Group C - only dropping points in a 1-1 home stalemate against Roma - and Pellegrini's men shipped just four goals en route to a first-placed finish.
Betis have never progressed beyond the last-16 of the Europa League in its current format - losing to eventual winners Eintracht Frankfurt at this stage last season - but Pellegrini's side travel to Old Trafford having only lost two of their last 12 away games in all tournaments, winning eight of them.
Thursday's first leg will mark the first-ever competitive meeting between Man United and Real Betis in any tournament, but the Verdiblancos have just one win to show from their previous six games against English opposition, and the wounded Red Devils should not prove easy pickings at their fortress.
Manchester United Europa League form:
W
W
W
W
D
W
Manchester United form (all competitions):
D
W
W
W
W
L
Real Betis Europa League form:
W
W
W
D
W
W
Real Betis form (all competitions):
L
L
W
W
W
D
Team News
Still coping without long-term absentees Donny van de Beek and Christian Eriksen, Man United have now been handed a fresh concern over Casemiro, who was noticeably off his game at Anfield and reportedly picked up an injury in the process.
The Brazilian will be assessed ahead of kickoff alongside Victor Lindelof, who missed Sunday's defeat with a minor unspecified problem, while Ten Hag is refusing to put a timeframe on Anthony Martial's recovery as he battles a hip problem.
A refresh should certainly be in order after such a humbling evening against Liverpool, with Aaron Wan-Bissaka, Harry Maguire and Tyrell Malacia potentially coming into the backline, especially with Luke Shaw and Raphael Varane emerging as doubts before kickoff at the weekend.
Meanwhile, Betis boss Pellegrini recently suffered a devastating blow with key attacker Nabil Fekir, as the Frenchman - who was recently linked with Man United - has been ruled out for the remainder of the season with an anterior cruciate ligament injury.
Midfielder Juan Cruz is also expected to miss out after exacerbating an existing muscular problem, but on a brighter note, Sergio Canales trained on Monday after missing the draw with Real Madrid with a quadriceps issue.
No fewer than four Real Betis players are walking a tightrope here, as Claudio Bravo, German Pezzella, Luiz Felipe and Aitor Ruibal will miss the second leg if they are cautioned at Old Trafford.
Manchester United possible starting lineup:
De Gea; Wan-Bissaka, Maguire, Martinez, Malacia; Sabitzer, McTominay; Sancho, Fernandes, Garnacho; Rashford
Real Betis possible starting lineup:
Bravo; Sabaly, Felipe, Pezzella, Miranda; Carvalho, Rodriguez; Canales, Rodri, Perez; Iglesias
We say: Manchester United 2-1 Real Betis
With a refreshed XI taking on a Fekir-less Real Betis side - who are not always adept at keeping things tight at the back - the stage is set for a confidence-rocked Man United to continue their Old Trafford excellence and return to winning ways.