Messi has not featured since suffering knee ligament damage against Las Palmas on September 26, but hopes had been raised that he could start after he played a full part in training this week.
However, with Barca leading Madrid by three points at the top of the table, Enrique has opted to ease his star man back into action with Sergi Roberto starting in attack alongside Luis Suarez and Neymar.
Barca coach to take late decision over Messi fitness
By contrast, Real Madrid boss Rafael Benitez recalled Karim Benzema to his starting line-up after six weeks out with a hamstring injury.
It is also Benzema's first appearance since the striker was charged with complicity to blackmail and conspiring to commit a criminal act in his native France in a case involving a sex tape featuring international teammate Mathieu Valbuena.
Benzema is reunited with Gareth Bale, on his 100th Real Madrid appearance, and Cristiano Ronaldo up front.
Meanwhile, Colombian star James Rodriguez is preferred to Casemiro in the Madrid midfield.
El Clasico: Full squad available to Benitez ahead of home game
Real Madrid (4-3-3):
Keylor Navas; Danilo, Raphael Varane, Sergio Ramos, Marcelo; Toni Kroos, Luka Modric, James Rodriguez; Gareth Bale, Karim Benzema, Cristiano Ronaldo
Barcelona (4-3-3):
Claudio Bravo; Dani Alves, Javier Mascherano, Gerard Pique, Jordi Alba; Sergio Busquets, Andres Iniesta, Ivan Rakitic; Sergi Roberto, Luis Suarez, Neymar.
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