Real Madrid's 2-1 victory over Valencia earlier in the afternoon had seen Los Blancos rise to the summit, but Barcelona are back on top due to their superior head-to-head record over the Madrid giants.
Barcelona boss Luis Enrique made five changes to the team that thumped Osasuna on Wednesday night, with Neymar and Luis Suarez among those to return, while a switch to a 4-3-3 formation opened up spots for Sergi Roberto and Jordi Alba.
As for Espanyol, head coach Quique Flores made just the one change to the team that drew 1-1 with Sporting Gijon on Tuesday night, and that came in defence as skipper Javi Lopez replaced Marc Navarro.
Espanyol had a golden chance to take the lead in the fifth minute when Felipe Caicedo raced away from the Barcelona midfield before feeding Jose Jurado inside the away side's penalty box, but the number 14 could only send his low effort wide of the far post.
Barcelona had a couple of half-chances in the opening 15 minutes of action, although Neymar's goal-bound strike was blocked by Javi Lopez, before Ivan Rakitic's dipping effort deflected just over Diego Lopez's crossbar as a tight Catalan derby remained goalless in the early exchanges.
Javi Lopez's work down the right became a feature of the first period for Espanyol, although Caicedo failed to meet a couple of dangerous crosses from the defender as Barcelona's back four were targeted by an opponent once again.
Barcelona's best chance of the first period came five minutes before the interval when Neymar found the head of Roberto with a brilliant cross from the left, but the full-back's effort was into the side-netting.
The pressure from the visitors continued into the final stages of the half, although Espanyol were largely comfortable as the pair headed into the half-time break on level terms following an uneventful first 45 minutes.
Barcelona were ahead in the 50th minute, however, when Luis Suarez raced onto an awful back-pass from Jurado before beating Diego Lopez at his near post. After restricting the Spanish champions to very little in the first period, it was a moment of madness from Jurado that saw the home side concede.
Neymar thought that he had doubled Barcelona's lead on the hour when he curled a brilliant effort towards the far corner of Espanyol's goal, but a wonderful save from Diego Lopez kept the score at 1-0.
The Spanish champions were purring, however, with Neymar, back from suspension, causing all sorts of problems down the left as he continued to cut inside and link with Luis Suarez and Messi.
Messi bent a free kick into the arms of Diego Lopez 20 minutes from time as the visitors looked to double their lead, but a double change from Espanyol, which saw Leo Baptistao and Hernan Perez enter, suggested that the hosts were not finished.
Barcelona netted a killer second in the 76th minute, however, when Rakitic slotted the ball into the bottom corner after an individual run from Messi had caused panic in the Espanyol defence.
The visitors were not finished, though, and scored a third through Luis Suarez in the 87th minute after the Uruguay international had pounced on a loose clearance from young full-back Aaron Martin.
Next up for Barcelona is a home game against Villarreal next Saturday, while Espanyol will look to bounce back when they visit Deportivo La Coruna on Sunday afternoon.