Manuel Pellegrini's side will be aware of the size of their task in the knockout round of the competition, with Man United eliminating runaway La Liga leaders Barcelona in the playoff round.
Real Betis will bring a four-game unbeaten run into this match, though, including a goalless draw with Real Madrid in the league last weekend.
The second leg of the last-16 contest will take place in Seville next week, so a positive result for the Green and Whites at Old Trafford on Thursday would put them in a strong position to reach the next round.
With that in mind, Sports Mole picks out three Real Betis players to look out for during the European clash in Manchester.
Borja Iglesias (Striker)
Borja Iglesias is Real Betis' leading goalscorer in all competitions this season with 10, all of which have come in La Liga, with Pellegrini's side chasing a top-four finish in the division this term.
The Spaniard has featured on four occasions in the Europa League but is yet to find the back of the net.
Willian Jose has actually been the starting forward in Europe this season, with the 31-year-old scoring twice in six appearances in the competition.
However, it would not be a surprise to see Iglesias introduced into the XI at Old Trafford, and the Spain international certainly has the quality to cause Man United's defence plenty of problems on Thursday.
Sergio Canales (Midfielder)
Real Betis were handed a huge fitness boost when Sergio Canales was declared fit for this match, as he had been a major doubt due to a recent injury.
Indeed, the 32-year-old has missed his side's last two league games due to a fitness issue, but he is in the squad for Thursday's match and is set to feature in the first XI.
Canales, who was once regarded as one of the best young talents in world football during his time at Real Madrid, has scored six goals and registered two assists in 28 appearances this season.
The Spaniard largely operates in an attacking midfield area, but he has featured off the right and off the left this term, and it will be fascinating to see where he plays at Old Trafford.
Canales has scored twice in the Europa League this season, meanwhile, and he will be looking to find the space between Man United's defenders and midfielders in the first leg of their last-16 affair.
William Carvalho (Midfielder)
William Carvalho will serve a La Liga suspension against Villarreal on Sunday due to the booking that he picked up against Real Madrid last weekend, but the experienced midfielder is available for this European contest.
The Portugal international has again been a vital player for the Green and Whites this season, playing 29 times in all competitions, including five appearances in the Europa League.
Only Luiz Henrique (31) has made more appearances for Real Betis this season than Carvalho, who was heavily linked with Man United in the early stages of his career.
Now 30, the midfielder has been a vital player for his Spanish club since arriving from Sporting Lisbon in July 2018, while he has been capped on 80 occasions by his national team.
Real Betis will need to be defensively sound to stand a chance of picking up a strong result on Thursday, and there is no question that Carvalho is a huge part of their set-up.
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