It means that for the first time in 11 years, a Barcelona-Real Madrid fixture will not feature Messi or Cristiano Ronaldo, now at Juventus of course.
He had already scored, making it 2-0 with a crisp left-footed finish, to add to a stunning opener from Philippe Coutinho.
After Sunday's clasico, Messi also stands to miss a Copa del Rey match against Cultural Leonesa, the return leg against Inter and league contests with Rayo Vallecano and Real Betis leading up to the next worldwide break.
"Football matches are won by scoring goals and not according to who deserves to win", said Lopetegui, who is only three months into his stint with the club after being fired from Spain's national team.
Lionel Messi suffered a fractured arm after an awkward fall in Barcelona's 4-2 win over Sevilla on Saturday and he stands to miss some crucial matches as a result.
However, Barca's medical staff will not rush Messi back, even for such an important game as Madrid, and he will likely remain sidelined for the estimated three weeks.
"We will notice his absence", Barcelona coach Ernesto Valverde said.
Marcelo pulled one back in the second half as Real pressed desperately to end their slump, but couldn't find a way past Oier Olazabal in the visitors' goal.
He stopped two certain goals of Sevilla with double saves from point blank ranges and put a few of Andre Silva's headed opportunities out of the Barcelona net. "I am thinking only about lifting the players". "We have a host of forwards who can lead the games for us".
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