Julen Lopetegui's side have beaten Ciudad de Lucena and Linares Deportivo to advance to this stage of the competition, while Leganes have overcome Ourense CF and Socuellamos to reach the round of 32.
Leganes have never won the Copa del Rey, but they actually reached the semi-finals of the competition in 2017-18 and have been present in the round of 16 in each of the last two campaigns.
Los Pepineros spent four seasons in La Liga between 2016 and 2020 before being relegated at the end of 2019-20, with the club now operating in the second tier of Spanish football.
The home team, as mentioned, have overcome Ourense and Socuellamos to advance to this stage, but they will be the underdogs to beat the Europa League winners this weekend.
Leganes have lost their last two matches with Sevilla but did record a 3-0 victory at the Estadio Ramon in May 2019 and will be expecting the visitors to rest a number of their key players on Saturday.
Sevilla, meanwhile, will enter the contest off the back of a 2-0 defeat at Atletico Madrid on Tuesday night, which left Lopetegui's team down in sixth position in the table.
The Europa League holders have only actually lost one of their last 10 matches in all competitions, with the run including victories over Ciudad de Lucena and Linares Deportivo in this competition.
Los Nervionenses have won the Copa del Rey on five occasions, the last of which was in 2009-10, while they were beaten finalists in 2017-18, with Barcelona triumphing by five clear goals.
Sevilla were knocked out in the round of 16 last term, though, and will certainly view La Liga and the Champions League, where they face Borussia Dortmund, as more important during the 2020-21 campaign.
Leganes Copa del Rey form: WWWLWW
Leganes form (all competitions): DLWDDW
Sevilla Copa del Rey form: WWWLWW
Sevilla form (all competitions): WWDWWL
Leganes possible starting lineup:
Riesgo; Rubio, Omeruo, Gonzalez, Lasure; Perea; Eraso, Munoz, Ojeda, Bua; De la Fuente
Sevilla possible starting lineup:
Bono; Vidal, Rekik, Gomez, Acuna; Torres, Gudelj, Rodriguez; Idrissi, De Jong, Munir
We say: Leganes 1-2 Sevilla
Leganes are certainly capable of causing Sevilla plenty of problems this weekend, but the strength of the La Liga club's squad means that it is difficult to back against them; we are expecting a tight game but fancy Lopetegui's side to secure a spot in the last-16 stage of the competition.