Both sides are likely to, along with Villarreal, battle it out for the fourth and final UEFA Champions League berth in Spain's top flight this season.
While La Liga leaders Real Madrid are only six points ahead of the fourth-placed Sevilla, it appears likely that Carlo Ancelotti's men will finish in the top three, alongside Barcelona and defending champions Atletico Madrid.
That leaves just one place to scrap over, and Sevilla are just one point ahead of Valencia in an exciting battle.
That could all change by the end of the Mestalla clash, with recent history also giving Valencia incentive.
Sevilla knocked Valencia out of the UEFA Europa League semi-finals last term, needing a stoppage-time goal from Stephane M'Bia in the second leg to send them through to the showpiece.
Sevilla then beat Benfica - who Gomes left to join Valencia in the close-season - in the final on penalties.
"Every game is a big deal to us but there are some that [are] more special" Gomes told Valencia's official website ahead of the match.
"It's going to be a fight to the finish against Sevilla and a few other teams until the end of the season.
"Sevilla are not the only big rival we have. The important thing is that we have the mentality to win.
"The second half of the season is just beginning. It is essential to be in winning form and get three points."
Sevilla have a Copa del Rey quarter-final first leg at Espanyol to contend with on Thursday, meaning Valencia should enter the match the fresher of the two sides.
Both sides are unbeaten in their last six league clashes.
At the top of the table, Real Madrid visit 14th-placed Cordoba and will feel confident about making it three wins in a row.
Real lead second-placed Barcelona by one point.
Luis Enrique's men, who beat Atletico Madrid 1-0 in their Copa del Rey quarter-final first leg on Wednesday, go to Elche.
Barca defeated Elche 9-0 on aggregate in the Copa del Rey's last 16 earlier this month.
Rayo Vallecano sit 10th in the league despite having the third-worst defence but they will need to be tight at the back when they visit Atletico Madrid.
Rock-bottom Granada go to fellow strugglers Deportivo La Coruna, while Levante and Almeria - also in the relegation zone - visit Villarreal and Espanyol respectively.
Athletic Bilbao will look to end a six-match winless streak against Malaga on Sunday.
Elsewhere, Real Sociedad battle Eibar and on Monday, Getafe welcome the visit of Celta de Vigo.
