Betis's top scorer Loren Moron snatched an equaliser for the hosts towards the end of the first half, volleying in from close range.
Sevilla restored their lead 10 minutes into the second period through Dutch striker Luuk de Jong and withstood waves of late pressure to grind out the victory, prompting wild celebrations from Lopetegui on the sidelines.
Meanwhile, Atletico Madrid were also on the winner's circle as they registered a 3-1 win over Espanyol at home.
Sergi Darder gave a surprise lead for the visitors in the 37th minute. Atleti drew level through Angel Correa in 45th, took the lead with Alvaro Morata's strike in the 57th before Koke gave them a comfort goal in the 90th.
Earlier, Lionel Messi delivered an incredible dead-ball hat-trick to steer Barcelona to a 4-1 victory over Celta Vigo and ease the pressure on his coach Ernesto Valverde.
A 34th treble in La Liga puts Messi equal with Cristiano Ronaldo, while a much-needed win send Barcelona above Real Madrid on goal difference and back to the top of the table.
Real Madrid had briefly claimed first place after continuing their own goal-surge by hammering Eibar 4-0, a game in which Karim Benzema scored twice and Eden Hazard exploded into life.
Benzema's double takes him to 157 goals for Real Madrid, above Ferenc Puskas into sixth in the club's all-time list.