The Sevilla-based club had been on a poor run before the tricky away assignment, even being booed off the pitch by their own fans at the weekend after a 1-0 loss to Real Valladolid.
However they showed their class against a star studded Milan team, which saw them take charge of Group F with seven points from three games.
A fairly even opening to the game saw both teams waiting for the other to make the first mistake and it was Milan who did.
Giovani Lo Celso was played in down the left and good persistence saw him get into the box to deliver into the middle.
Experienced goalkeeper Pepe Reina really should have claimed the cross, but a mix up saw the former Liverpool man miss the ball and Antonio Sanabria was on hand to poke the ball into the empty net for his second Europa League goal of the season.
The score remained the same until after the break, but 10 minutes after the teams reemerged for the second half, Argentina midfielder Lo Celso showed his class with a stunning curling strike that beat Reina from long range.
From here on out Betis looked like they would see out the game, but a late strike from Parick Cutrone made it a nervy finish for the men in green and white.
Samu Castillejo had set up the goal with an incisive dribble and pass, but he left the pitch in disgrace in the 94th minute after a petulant and late challenge on Lo Celso left the referee with no choice but to send him off.
Betis ended the night as deserved winners and put themselves in pole postion to qualify from their group.