Lille started strongly and took the lead through Ayase Ueda, who headed in his second goal in as many games after a well-weighted delivery from Ethan Mbappe.
Betis responded when Marc Bartra met Pablo Fornals' whipped cross with a diving header, only for Lille to regain their advantage before half-time through Alexsandro's header from Gaetan Perrin's corner.
The Spanish side levelled again just three minutes after the restart when Bartra got a slight touch to Isco's free-kick, directing the ball beyond Berke Ozer.
Former Tottenham striker Troy Parrott completed the comeback in the 53rd minute, taking the ball around 30 yards from goal before advancing and firing a low left-footed effort into the far corner.
Parrott also scored the only goal in Betis' LaLiga victory over Real Madrid on Friday, continuing his impressive start since joining from AZ Alkmaar for 16 million euros last month.
"I'm really happy for Troy, scoring two goals in two matches is huge for him," Betis coach Manuel Pellegrini said.
Lille's hopes of recovering were further damaged three minutes later when Mbappe, brother of Real Madrid star Kylian, was shown a straight red card after appearing to elbow Betis defender Natan in the face.
The hosts continued to push despite being reduced to 10 men and brought on former Arsenal and Chelsea striker Olivier Giroud among their attacking reinforcements.
Betis, though, withstood the late pressure to secure three points on their return to the Champions League after a 21-year absence.
Borussia Dortmund defeated Villarreal 3-2 in their UEFA Champions League opening clash at the Signal Iduna Park on Tuesday evening after a Serhou Guirassy double strike.
Aston Villa scored three goals in the first half and then held on to beat Club Brugge 3-2 in their UEFA Champions League opener in Belgium on Tuesday.
Dominik Szoboszlai is relishing his growing leadership role at Liverpool and believes Andoni Iraola's high-intensity football can help the Reds become a team opponents fear.
Bayern Munich are aiming high once again, with Konrad Laimer making it clear that the Champions League remains a major target as Vincent Kompany's side look to challenge for another trophy-filled season.
