The Red Devils were looking to return to winning ways after losing 4-2 to Cadiz on Wednesday, but they were fortunate to head into half time with the score still goalless following a number of Betis chances, including a Paul Akouokou effort which struck the post.
Betis were able to find the opening in the 49th minute when Nabil Fekir beat substitute goalkeeper Tom Heaton with a curling effort that proved to be the decisive goal, ensuring Betis secured a 1-0 victory.
Although the World Cup left Erik ten Hag without a number of first-team regulars, the Dutchman was still able to call upon the likes of David de Gea, Aaron Wan-Bissaka, Victor Lindelof, Scott McTominay and Anthony Martial.
Although, the United boss was forced into a late change prior to kick off, with Isak Hansen-Aaroen replacing Donny van de Beek.
Meanwhile, Betis named a strong lineup that included Sergio Canales, Borja Iglesias and Fekir, and it was the hosts who started the game on the front foot.
Brandon Williams cleared the ball off the line in the early stages to prevent from the Spanish side from opening the scoring.
The 20-time English champions received a blow in the 19th minute when Teden Mengi was stretchered off with what appeared to be a hamstring injury.
Betis continued to press forward in search of opener, and they went agonisingly close to finding the net when Luiz Henrique laid the ball into the path of Akouokou, who struck the post with a driven effort.
With chances proving to be few and far between for the Red Devils, Anthony Elanga took it upon himself to try his luck from range, but his low strike travelled harmlessly wide of the Betis goal.
Iglesias has scored eight goals in 13 La Liga matches this season, and he had the chance to showcase his finishing ability in the 34th minute, however, his powerful strike flew over De Gea.
The final opportunity of the opening 45 fell the way of Martial, who bent an effort from the edge of the box wide of the Betis goal.
United made four changes at half time, including Heaton for De Gea, and the substitute goalkeeper was called into action within the opening 20 seconds of the second period to deny Henrique.
Unfortunately for the Red Devils, there was nothing that Heaton could do to prevent Fekir from curling the ball into the far corner only moments later
As Betis searched for a second, Iglesias attempted to catch Heaton off his line with an ambitious effort, but his long-range strike drifted over the bar, before the United goalkeeper made a comfortable save to thwart Alex Moreno.
Although United were enjoying spells of possession, they were struggling to create clearcut chances, despite Noah Emeran bending the ball past the post.
With both sides continuing to make changes as the game progressed, the second half petered out without much fuss, ensuring Betis held on to claim a narrow win
United will now turn their attention to a League Cup tie with Burnley on December 21, while Betis will prepare for two more mid-season friendlies against Inter Milan and Atalanta.