Goals by Sergio Garcia and Diego Colotto ensured Espanyol wrapped up a notable double, having beaten Athletic in September's reverse fixture, and also making it back-to-back league wins after their 1-0 victory over Granada last time out.
Carlos Gurpegi hit Athletic's reply early in the second period but it could not fire the hosts to an improved overall performance and Colotto duly made them pay with the winner after 65 minutes.
Aritz Aduriz was sent off late on to wrap up a miserable night for the hosts, whose unbeaten home run in La Liga came to an end at the 13th time of asking. Athletic had won nine of their previous 12 league matches at their new home, although they did lose to Atletico Madrid in the Copa del Rey.
Esponyol stunned the home fans as they went ahead with just six minutes gone, Simao Sabrosa playing in Garcia who made no mistake with a low drive into the left corner.
The visitors were almost pegged back just before the half-hour when Ibai Gomez's free-kick was met with a superb diving header by Gurpegi but Francisco Casilla produced a fine save to turn the ball away.
Esponyol's lead was nearly doubled in the 38th minute but Christian Stuani saw his effort from close range come back off the post.
The hosts needed just 12 minutes of the second period to bring the scores level, Gomez again combining with Gurpegi from a set-piece, with Casilla on this occasion unable to keep out the defender's header.
But the home side were only level for eight minutes before Espanyol took the lead for a second time, Simao's inswinging corner finding its way into the net off Colotto, who did not appear to know too much about it but celebrated as if he meant it.
The visiting side continued to press and very nearly made it three in the 75th minute when Stuani broke away down the right channel and fired in a low shot across goal that Gorka Iraizoz cleared with a firm hand down low.
Stuani had another chance in the 84th minute but fired wastefully at Iraizoz when a placed effort surely would have found the target, while moments later Athletic's hopes were as good as over as Aduriz received his marching orders after picking up a second caution for a foul on Victor Sanchez.