Betis's strong start to the Spanish season continued, courtesy of goals from Cucho Hernandez and Natan.
The side's victory on Monday (Tuesday AEST) came 10 days after they beat Real Madrid 1-0 in La Liga, and less than a week after they overcame Lille 3-2 in their first Champions League group match since 2005.
The result at Estadio de la Ceramica lifts Betis into second place, tied with Madrid on 12 points. Barcelona are top on 15.
It was another disappointing night for the home side, who are still to win this season and sit third-bottom with just two points from five matches.
Meanwhile, the top two in Italy, Roma and Inter Milan, each won comfortably to maintain their 100 per cent records, and Como beat Parma 2-1 to climb into third spot.
Roma continued their superb start to the season with a 2-0 win over Torino.
They were joined at the top of the table by the only other team with maximum points, Inter Milan, who came from behind to beat Udinese 5-3.
Both teams have 12 points from four games, although Roma are first on goal difference after what was their ninth consecutive victory.
In-form striker Donyell Malen scored his sixth goal in four games to put Roma ahead, and Niccolo Pisilli got a deserved second in stoppage time.
Inter struggled to get going against Udinese, who looked set to continue their good run of away form by scoring twice without reply in the opening 16 minutes.
James Abankwah rose unmarked to head Udinese ahead in the ninth minute, and Jurgen Ekkelenkamp doubled their lead seven minutes later.
However, Carlos Augusto got a goal back for the reigning champions after 26 minutes with a 30-yard strike, and Nicolo Barella equalised 10 minutes before halftime.
In Como, the home side moved into the top three with a 2-1 win over Parma.
Jacobo Ramon turned Nico Paz's shot in for the opener midway through the first half, and Kaiki made it 2-0 seven minutes from time after a goalmouth scramble.
Jose David Romero got Parma's consolation in stoppage time.
Como are third on 10 points, equal with Lazio.
