The two sides have a combined 13 Copa del Rey trophies and both could see this year as a great opportunity to add another domestic cup to their trophy cabinet after the shock exit of Real Madrid in the last round, and the potential weakness of Barcelona.
Sevilla coasted through the first two rounds of the tournament, beating lower league opposition in Ciudad de Lucena and Linares Deportivo 3-0 and 2-0 respectively away from home.
The third round was a closer tie for Julen Lopetegui's side as they travelled to Segunda Division outfit Leganes, who were relegated from La Liga last season.
Neither side managed to break the deadlock inside 90 minutes and the game went to extra time, when Lucas Ocampos netted the only goal to secure Sevilla's spot in the last 16.
This could be an important game for Sevilla manager Lopetegui, who is aiming for his 50th win in charge of the club.
Since his appointment in 2019, the Spaniard has taken charge of 83 matches, winning 49, drawing 19 and losing just 15. This has resulted in a Europa League trophy and a strong fourth-placed finish in La Liga last season, level on points with third-placed Atletico Madrid.
Their good form under the former Spain and Real Madrid manager has continued into this season, where his side sit in fourth once again, having won 11 of their 19 league games so far and losing just five of these matches.
This has been in no small part down to the effects of Moroccan forward Youssef En-Nesyri, who has netted 12 league goals and sits joint-top of the league's scoring charts with Luis Suarez. This includes a hat-trick in their last fixture with the striker being the only scorer in a 3-0 home win over Cadiz in La Liga, seeing them leapfrog Villarreal in the league table.
Sevilla have already posted a win over Wednesday's opponents this season, defeating Valencia 1-0 away at the Estadio de Mestalla. The game looked set to finish 0-0 until Suso made the breakthrough for the visitors from outside the box in the final 10 minutes.
That was one of eight league defeats suffered by Valencia so far this term and, since the sale of several key players at the beginning of the campaign, they have experienced a dramatic fall down the table from last season's ninth-placed finish, which followed two consecutive years of finishing fourth.
As a result of their poor first half of the season, they currently sit 14th in the La Liga table, just two points above Alaves in the relegation zone, on 20 points from their 20 league games.
Javi Gracia's side have just one win in their last 11 La Liga fixtures. However, he may have a reason to be optimistic as in all competitions, Valencia have recorded three wins and two draws in their last six games, with their only defeat in this run being a 3-1 loss at the hands of La Liga leaders Atletico Madrid.
Their Copa del Rey campaign got off to a very worrying start in their first-round tie away at fourth-tier side Terrassa. The hosts went 2-0 ahead early in the second half but two goals in the last 10 minutes through Carlos Soler and Yunus Musah took the tie to extra time. Goncalo Guedes then found the net twice to take his side through to the next round with a 4-2 win.
The second round was much more comfortable for Gracia's side as they beat Segunda Division B side Yeclano 4-1 away from home. Another comfortable win then followed as Koba Koindredi and Manu Vallejo fired Valencia to a 2-0 win away at second-tier side Alcorcon, booking a ticket in the round of 16.
The eight-time Copa del Rey champions will be hoping to use these convincing wins as foundations to build on as they take on their toughest cup challenge so far this season as Los Che look to regain the trophy they won back in 2019.
Sevilla Copa del Rey form: WWW
Sevilla form (all competitions): WWLWWW
Valencia Copa del Rey form: WWW
Valencia form (all competitions): DWWWDL
While no player has more La Liga goals than Youssef En-Nesyri this season, the Moroccan has rarely been called upon in cup action, only appearing in a cameo in the second-round victory over Linares.
So far, Luuk de Jong has started all three Copa del Rey fixtures and is likely to be trusted in this clash too, as Lopetegui has to balance a league game against Eibar three days later.
Sevilla defender Diego Carlos is expected to still be unavailable after a positive COVID-19 test.
Valencia defender Mouctar Diakhaby was forced off at half time in the 3-1 loss to Atletico Madrid and is expected to miss this clash, while goalkeeper Jasper Cillessen remains out of the squad with a muscle injury.
Defender Cristiano Piccini also returned to the Valencia squad after a loan spell with Atalanta, where he made just one appearance, while they were recently also boosted by the return of Kevin Gameiro who will be hoping for a first start since his return, after two appearances off the bench in their last two games.
Sevilla possible starting lineup:
Bono; Vidal, Gomez, Kounde, Rekik; Fernando, Oliver, Gudelj; Suso, De Jong, Munir
Valencia possible starting lineup:
Domenech; Correia, Guillamon, Mangala, Piccini; Guedes, Racic, Koindredi, Musah; Vallejo, Gameiro
We say: Sevilla 2-1 Valencia
While Valencia may have some real confidence and optimism for one of the first times this season, we feel that the home side may have too much quality and could punish Gracia's men with the attacking quality of Munir El Haddadi and Suso with Luuk de Jong down the middle. Lopetegui could see a real opportunity for a domestic trophy here and won't underestimate their opponents.