The club have never recovered from a first-leg home defeat to win a tie in UEFA competition, so the odds appear heavily stacked against Sevilla as Betis boast a 2-0 lead heading into the return game.
Goals from Leo Baptistao and Salva Sevilla settled matters in the first leg of the last 16 tie and earned Betis a first win against Sevilla since May 2012.
Buoyed by two away goals and a clean sheet at the Estadio Ramon Sanchez Pizjuan, Betis stand on the verge of the last eight of a UEFA competition for the first time since progressing to the quarter-finals of the Cup Winners' Cup in 1997-98, where they lost to eventual winners Chelsea.
Factor in that the last three derbies at Betis have ended all square and that La Liga's bottom club have lost just once in 11 Europa League outings this season, and the task awaiting Sevilla looks daunting.
Unai Emery, though, will take heart from Sevilla scoring 12 goals in the three games against Betis prior to last's clash, but their hosts are unbeaten in five European home games since the start of this season and have only conceded once in that run.
Defender Jordi Figueras, who played the full 90 minutes in the first leg, has urged his Betis team-mates that a professional performance is required to complete a memorable European success against their arch rivals.
"We have the advantage that we got in the first leg, and we must be smart to win the game," he said.
"The tie is open. The (first leg) result for us was great, but we will not be foolish and relax because that can take its toll.
"It would be a mistake to defend for 90 minutes, they (Sevilla) have to take risks and we know we have quality players to get to ball up and we can catch them."
Sevilla will be without Uruguayan midfielder Sebastian Cristoforo, who faces six months on the sidelines with a serious knee ligament injury, and the suspended Vicente Iborra.
Betis are sweating on the fitness of Baptistao as Gabriel Calderon welcomes back Nono after he missed the first leg.
Sevilla bounced back in some style to last Thursday's defeat by thrashing Real Valladolid 4-1 at home to make it four Liga wins on the spin, lifting them up to seventh.
The hosts are undefeated in their last five in all competitions but sit bottom of the table, nine points from safety.
