The Blaugrana will reportedly attempt to sign Isco if he doesn't sign a contract extension at the Bernabeu, reports in Spain claim.
Barcelona are reportedly monitoring Isco's contract situation at Real Madrid.
The former Malaga playmaker's current deal at the Bernabeu expires in 2018 and an extension isn't thought to be close.
Spanish outlet Mundo Deportivo say Barca are one of the clubs interested in signing Isco if he doesn't renew his contract with Madrid.
Isco joined Los Merengues from Malaga in 2013 for £40million but has struggled to nail down a regular spot in the team over a three-and-a-half year period at the club.
He is currently enjoying a good run in the side, though, with Zinedine Zidane using him in each of Madrid's last seven La Liga matches.
Zidane could hand the 24-year-old even more game time over the coming months, with Gareth Bale sidelined until next year with a serious ankle injury.
Javier Saviola was the last player to move directly between Spain's two most successful clubs, joining Madrid from Barcelona in 2007.
Before that, Luis Figo became the world's most expensive player in 2000 when he joined Madrid from Barcelona in a £37million transfer.
It is claimed Barca see Isco as the natural successor to Andres Iniesta, who is eight years his senior.
There are three options for Madrid with regard to Isco's future: renew his current contract; sell him before his current deal expires to ensure they receive a transfer fee for him; or let him leave for free when his contract runs out in the summer of 2018.