Guzman, who headed Mexico's notorious Sinaloa Cartel and once made it on to Forbes' list of billionaires, was arrested last year. He last escaped from prison in 2001 after a prior capture in 1993.
Guzman was seen on video entering a shower area at 8.52 p.m. local time on Saturday, Mexico's national security commission (CNS) said in a statement, Reuters repoted. After he went out of view for a while, guards entered his cell to find it empty.
The CNS statement gave no details on how Guzman had managed to escape, and a government spokesman could not immediately provide further clarity on the matter.
National Security Commissioner Monte Alejandro Rubido is due to give a statement at 7 a.m., the interior ministry said.
Flights have been suspended from the city of Toluca's airport, near the Altiplano prison, and security officers have started searching roads near the site in the State of Mexico, about 90 km (60 miles) west of the capital, the CNS said.
Guzman became one of the world's most powerful organized crime bosses, running a cartel that smuggled billions of dollars worth of cocaine, marijuana and methamphetamines into the United States and fought vicious turf wars with other Mexican gangs.
In 2001, the drug lord escaped the Puente Grande prison, near the city of Guadalajara. According to reports at the time, he left hiding in a laundry cart.