Three days after winning 3-0 at Bernabeu Stadium in the semifinals of the Copa del Rey, Barcelona followed up by defeating Madrid 1-0 to virtually end its hopes of winning the La Liga title.
Another disappointing result would also send the team into a crisis entering the final stretch of the season, with coach Santiago Solari likely paying the highest price.
After Copa del Rey semifinal defeat Real Madrid's task is harder. They have only three days to piece themselves back together for another Clasico.
Luis Suarez scored twice as Barcelona advanced 4-1 on aggregate after being held to a 1-1 draw in the first leg of the semifinals at Camp Nou.
Gareth Bale has recently come under some scrutiny for poor behaviour on and off the pitch.
Real Madrid and Barcelona will play each other twice within a week, starting with the second leg of the Copa del Rey semi-final on Wednesday at Santiago Bernabeu Stadium.
Messi regained his scoring touch just before the two decisive matches against Real Madrid.
Santiago Solari said Real Madrid would have a day less to prepare than its rival Barcelona ahead of their Copa del Rey El Clasico.
Lucas Vazquez gave Real Madrid the lead in the 6th minute before Malcom equalised for the hosts in the 57th minute to earn a draw at the Camp Nou.
With Barca quiet on Messi's injury, Madrid arrive for the first-leg match at Camp Nou enjoying its best period of the season and with nearly all of its players available.
It will be the teams' first Copa del Rey meeting since 2014 final, which Real Madrid won for its last title in the competition.
Messi underlined his importance to Barca again on Saturday night as he scored both goals to allow his side come back from 0-2 to claim a 2-2 draw against Valencia.
The first leg will be next week in Barcelona, with the return match in Madrid on February 27, just before their Spanish league game at Santiago Bernabeu Stadium on March 3.
Lopetegui was finally fired by Real Madrid on Monday, less than five months after he was sacked by Spain before the World Cup for not telling federation officials he accepted the Madrid job.
Luis Suarez scored a hat-trick as he led Barcelona to a 5-0 victory over arch-rivals Real Madrid in El Clasico on Sunday.
The victory lifted Barcelona back to the top of the Spanish league with 21 points, while Madrid were left languishing in ninth place with 14 points.
The victory lifted Barcelona back to the top of the Spanish league with 21 points, while Madrid were left languishing in ninth place with 14 points.
Highlights, El Clasico: Suarez's hat-trick helps Barcelona beat Real Madrid 5-1
The 18-year-old Real Madrid forward, who has not been a regular in the first team, had his suspension overturned on Friday.
Lopetegui's status as a top coach will be highly contested if he fails with Madrid not long after his abrupt departure from Spain's national team just before the World Cup.
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