An extra edge to Saturday's game is added by blaugrana coach Ernesto Valverde having played for and coached both clubs.
Espanyol coach Rubi, meanwhile, was on the coaching staff at the Camp Nou during the 2013-14 season.
Saturday's action begins elsewhere in the capital with third-placed Atletico Madrid hosting fourth-placed Alaves. It's likely to be a tight affair as the team from Vitoria have drawn two of their last three games, while Antoine Griezmann and company are unbeaten at the Wanda Metropolitano this term.
Next comes another historic clash as Valencia face Sevilla in a game always humming with rivalry between Spain's third and fourth biggest cities. Valencia's inconsistent start means getting a victory to make up ground in the table is even more important than usual, while second-placed Sevilla will know that another three points would put them temporarily back top of the La Liga standings.
Villarreal host Celta Vigo later on Saturday afternoon with both clubs still in the bottom half but showing recent signs of improving form. The Yellow Submarine have also scored nine goals in their last two games against Celta at the Estadio de la Ceramica.
Two of La Liga's most in-form sides meet in Sunday's game, with Eibar looking for a third straight win in front of their fans at Ipurua and visitors Levante unbeaten in their last four games on their travels.
Next up are bottom side Huesca, badly in need of a boost, who welcome Real Madrid and newly crowned 2018 Ballon D'Or winner Luka Modric to El Alcoraz for the first time ever in La Liga. Los Blancos have already been beaten on trips north to Eibar and Alaves this season, so will be out to avoid a nasty surprise.
Two teams looking to return to the top half of the table then meet at Anoeta, as a Real Sociedad team starting to click host a Real Valladolid side aiming for a first win in six La Liga games.
Sunday's final fixture has Rayo Vallecano travelling south to visit Real Betis in a fixture which usually promises goals: both of Rayo's last visits to the Benito Villamarin have ended in 2-2 draws.
To round of the matchday, Monday brings a first game as Athletic Club coach for former Los Leones player Gaizka Garitano. It's a tough debut: the visitors to Bilbao are a Girona side unbeaten away from home in LaLiga this season, with current Pichichi topscorer Cristhian Stuani in flying form (11 goals).