Messi has not played since the end of September, during which time champions Barca have pulled three points clear of second-placed Real at the top largely thanks to the form of the Argentina captain's fellow forwards and South American compatriots Neymar and Luis Suarez.
Messi, the all-time top scorer in 'Clasicos' with 21 goals in 30 matches, returned to training on Monday and coach Luis Enrique has opted to keep him in reserve, the first time the player has started a game against Real as a substitute.
Neymar and Suarez will operate in attack, with midfielders Andres Iniesta, Sergio Busquets, Ivan Rakitic and Sergi Roberto also included in the starting 11.
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A win at the Bernabeu for Barca, who are chasing a sixth La Liga title in eight years, would put them six points clear of Real after 12 matches.
Security around the stadium has been ramped up to what officials have said is unprecedented levels following last week's attacks in Paris.
More than 2,000 police and other security and emergency services personnel have been deployed, fans were subjected to rigorous checks before being allowed in and snipers were positioned on the stadium roof.
Some 80,000 fans will pack the giant arena in the Spanish capital, with an estimated 500 million more around the world watching what is probably soccer's biggest club fixture.
(Reporting by Iain Rogers, editing by Clare Fallon)
