Lionel Messi scored two goals and set up two more to lead Barcelona's 4-1 win over crosstown rival Espanyol, which finished a hot-tempered Copa del Rey clash with nine men on Wednesday.

Felipe Caicedo grabbed Espanyol a ninth-minute lead at Camp Nou, but Messi hit right back four minutes later.

The star forward put the hosts ahead with an unstoppable free kick just before halftime, and assisted Gerard Pique soon after the interval.

Messi then set up Neymar for the fourth goal after Espanyol's Hernan Perez and Papakouly Diop were sent off, and Caicedo and Marco Asensio were lost to injury.

Espanyol, which held Barcelona to 0-0 in the Spanish league on Saturday, will have the return leg of the round-of-16 tie at its stadium next week.

Elsewhere, Athletic Bilbao, last year's finalist to Barcelona, scored three times in the second half to erase a two-goal deficit and beat Villarreal 3-2, while Valencia, Sevilla, and Deportivo La Coruna got positive results.

Arda Turan and Aleix Vidal, used as a substitute, debuted for Barcelona, after the club finished its ban on new players during 2015 for breaking FIFA's rules regarding the transfer for youth players.

Espanyol found its opener when Caicedo used an excellent first touch before slotting in a ball he received from Asensio, who started a counterattack by intercepting Dani Alves' pass.

But Messi quickly responded when he caught Espanyol's defense off-balance after Andres Iniesta played him forward to beat goalkeeper Pau Lopez.

Caicedo went down holding his left thigh near halftime, but the visitors' defense held firm until Messi sent his free kick streaking in off the underside of the crossbar.

Espanyol's hopes took another blow when Asensio was substituted after he apparently picked up an injury during the halftime warm-ups.

It was all Barcelona the rest of the way, as Messi set up Pique to tap in his goal after Iniesta's incisive pass started the move.

Tempers flared as the game dragged on, with Messi, Neymar, and Suarez receiving yellow cards, along with eight for Espanyol.

Perez's second booking was followed by Diop seeing red for something he apparently said to Suarez in the 75th. The undermanned Espanyol resisted until Messi flipped the ball forward for Neymar to put in.

Bilbao fell behind at home after Villarreal scored twice on counterattacks, finished off by Leo Baptistao and Samuel Garcia. But Benat Etxebarria set up Inaki Williams to pull one back, striker Aritz Aduriz soon leveled, and Aymeric Laporte completed the comeback in the 81st.

"It's a deceptive result," said Aduriz, who scored his 22nd goal in 30 games across all competitions. "It looks like we won, but it is going to be very tough to make it hold up at their ground."

Gary Neville also got his first win as Valencia coach over a topflight team after Alvaro Negredo scored a hat trick in a 4-0 rout of Granada.

Valencia is still without a win through four Spanish league matches under Neville, and had previously beaten only a third-division team in the cup since the former Manchester United player took charge.

Sevilla took a 2-0 lead from its victory at Real Betis in a one-sided Seville derby, while Deportivo La Coruna needed defender Alberto Lopo to head in a late equalizer to claim an away-goal advantage from its 1-1 draw at second-division club Mirandes.

Atletico Madrid visited crosstown rival Rayo Vallecano late.

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