A massive manhunt is underway for Guzman, head of the Sinaloa Cartel, an international organization that reportedly controls most of the major smuggling points into the U.S. from Mexico.
Mexican authorities have grounded flights at the nearest airport and Mexican federal police are heavily patrolling the area and have set up checkpoints.
More than a dozen employees at the prison were being held for questioning.
Guzman, who was also the No. 1 most wanted criminal by the American DEA, was captured in 2014, after having been on the run from a different Mexican prison he escaped from in 2001. He was first captured in Guatemala in 1993.