Xavi Hernandez's side can win the league for the first time since 2019 if it emerges victorious at the RCDE Stadium, an unthinkable proposition for home supporters.
The Catalans can also lift the title if both second-place Atletico Madrid and third-place Real Madrid fail to win their matches against Elche and Getafe, respectively.
By contrast, Espanyol is fighting for its lives at the other end of the table, currently 19th and three points from safety with five games remaining.
It was relegated in 2020 for the first time in almost three decades but immediately returned to the top flight in 2021.
Espanyol became the first La Liga side to score at Camp Nou this season with a 1-1 draw against Barcelona in December, and only Real Madrid have accomplished the feat since.
Joselu struck a penalty to equalize that day and the Spanish international striker warned Barcelona that despite the teams' positions, in a derby there is a level playing field.
"In the first match they also came into it very strongly," Joselu told DAZN. "They (thought they) were going to put five against us at the Camp Nou and we got a very positive result. They have a lot of advantage over us coming into the second match, but in the end, a derby is a derby and you can see it all in derbies. One side can be better and another worse, but there, all strengths are leveled out."
Espanyol's defeat last weekend by Sevilla leaves Barcelona's "other" club in a precarious position.
"We have to keep fighting because there are games and points left, we will not give up," insisted defender Leandro Cabrera.
Of the clubs fighting relegation, Espanyol has arguably the worst remaining fixtures, though. As well as Barcelona's visit on Sunday, it hosts Atletico Madrid and Almeria at home, as well as visiting Rayo Vallecano and Valencia.
The last time Espanyol beat Barcelona in La Liga, coach Luis Garcia was playing for it, in February 2009 at Camp Nou.
Barca midfielder Sergio Busquets will likely feature in one of his last games for the club after announcing Wednesday he would leave at the end of the season when his contract expires.
The 34-year-old, who has featured over 700 times for the club, has five official matches remaining with the Catalan giants.
As a World Cup and European Championship winner with Spain, some Espanyol fans may be inclined to offer him farewell applause, but he won't be banking on it in enemy territory with so much at stake.
Player to watch: David Silva
The 37-year-old playmaker has been a key figure for Real Sociedad this season, with his performances a big reason for their climb to fourth place. Silva has agreed to stay for another season with the Basque side and can celebrate his contract extension on Saturday against Sevilla.
Saturday Real Sociedad vs. Girona, Osasuna vs. Almeria, Villarreal vs. Athletic Bilbao, Real Madrid vs. Getafe
Sunday Celta Vigo vs. Valencia, Elche vs. Atletico Madrid, Real Valladolid vs. Sevilla, Espanyol vs. Barcelona
Monday Real Betis vs. Rayo Vallecano (1900)
© Agence France-Presse