Second-half strikes from Antony, Bruno Fernandes and Wout Weghorst added to Marcus Rashford's early strike as the Red Devils claimed a comprehensive first-leg victory.
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Man United overpowered Betis following an impressive second-half display in this UEFA Europa League round of 16 first leg.
6': Rashford powers close-range opener
32': Pérez drills low equaliser
52': Antony hits delightful curling effort
58': Bruno Fernandes heads in corner
84': Weghorst turns in rebound after Bravo save
Match in brief: Strong second-half showing from United
United manager Erik ten Hag was hoping for a reaction following a club record-equalling 7-0 defeat against Liverpool on Sunday and kept faith with the same side.
It quickly paid dividends early on when the visiting defence were unable to clear a Bruno Fernandes cross following a quick United counter and Marcus Rashford powered a fierce right-footed effort into the roof of the net.
The in-form English international and Wout Weghorst both went close to adding to the home side's advantage, but were denied by former Manchester City keeper Claudio Bravo.
Manuel Pellegrini's men slowly gained a foothold back in the match and stunned the Old Trafford crowd just after the half-hour by scoring with their first attempt on target. On-loan Leicester forward Ayoze Pérez exploited the space afforded him to the right of the box to drill an impressive finish just inside the far post.
The home side regained control of the tie with two goals in the space of seven minutes shortly after the restart. Antony, collecting a pass from Bruno Fernandes, hit a virtual carbon copy of his winner against Barcelona in the last round with a delightful curling effort past the static Bravo.
Fernandes got on the scoresheet himself shortly afterwards, the United captain heading powerfully in from Luke Shaw's outswinging corner.
Weghorst – and United's – persistence paid off as they grabbed a fourth in the closing minutes, after Bravo could only parry a shot from substitute Scott McTominay.
Steve Bates, Man United reporter
Energy, intensity, passion and goals – Ten Hag couldn't have asked for more. The perfect response to the Liverpool defeat, United showed they're working again to the principles and mentality their manager demands. But despite a three-goal lead, they will know this tie is far from finished. Betis will be wounded and dangerous at the Estadio Benito Villamarin next Thursday.
Graham Hunter, Real Betis reporter
A salutary lesson for Betis here. They were diligent, hard to shake off and, increasingly, European-quality in their first-half display, particularly having gone 1-0 down. But they were caught cold, and not by the weather, after half-time. Their opponents upped the intensity, upped the creative risks they were willing to take and Pellegrini's experienced team didn't cope well. Not only were the rivals quicker and more ruthless – Betis contributed with lapses in possession which they'll rue badly.
Erik ten Hag, Man United manager: "I'm very pleased with the performance. We played very well in and out of possession. We had a good press, were compact pressing forward and made it difficult for the opponent to create. There was a lot of movement, and also the character of the team bouncing back after they made it 1-1."
Marcus Rashford, Man United forward: "We always try to start quick and a goal always helps that. They defended the box well in the first half, but in the second it opened up more – as to be expected with the game at 1-1. We started well in both halves. It is important to try and score the goals and that is the difference."
Manuel Pellegrini, Betis head coach: "We competed very well in the first half. Antony scored a great goal and then their third, from a corner, finished the game off. The game was decided in those minutes."
Ayoze Pérez, Betis forward: "This is tough to explain – particularly after the first half we produced against a top side like United."
Paul Scholes, BT Sport
"It showed great character tonight. United started the game really well but had a little sticky spell just before half-time. Second half they were fantastic, with Bruno Fernandes dictating play in the centre of the pitch."
- United are enjoying their longest unbeaten run in UEFA competition (eight matches) since an 11-game streak during their successful 2016/17 Europa League campaign.
- The Old Trafford club are now unbeaten in their last 14 home matches in the Europa League knockout phase (W10 D4).
- Rashford struck his 26th goal of the season – only Erling Haaland (33) and Kylian Mbappé (30) have scored more for a side playing in the top flight in England, France, Germany, Italy or Spain.
- The Red Devils have won 18 of their last 20 home matches in all competitions, drawing the other two.
Man United: De Gea; Dalot (Wan-Bissaka 46), Varane, Martínez, Shaw (Malacia 65); Casemiro, Fred (McTominay 82); Antony (Pellistri 82), Weghorst, Bruno Fernandes; Rashford (Sancho 65)
Real Betis: Bravo; Sabaly, Pezzella, Luiz Felipe, Abner Vinicius; Carvalho, Rodríguez (Guardado 65); Luiz Henrique (Ruibal 59), Joaquín (Canales 59), Juanmi (Willian José 80); Pérez (Borja Iglesias 65)
The second leg takes place in Seville on Thursday 16 March. The aggregate winners will enter the Europa League quarter-final, semi-final and finals draws on Friday 17 March.