"Escobar", a Spanish-Bulgarian joint project to be filmed in Colombia, will go into production on October 24 with Bardem playing Escobar and Cruz playing his lover, journalist Virginia Vallejo, producers said Tuesday in a statement.
"This is not a biopic, not just the story of a tough gangster. This is the story of the man who changed the history of crime in the last decades of the 20th century," the film's producer, Miguel Menendez de Zubillaga, said in the statement.
Husband and wife off screen, the last time the two appeared together in a movie was in the 2008 Woody Allen romantic comedy "Vicky Cristina Barcelona". Cruz won a supporting-actress Oscar for her role.
Bardem won a supporting-actor Oscar for the 2007 crime thriller "No Country for Old Men".
"Escobar" will be directed by Spain's Fernando Leon de Aranoa whose credits include the 2002 film "Mondays in the Sun" also starring Bardem, for which both got Spain's Oscar-equivalent Goya for best director and best actor.
Escobar was the boss of one of the world's most powerful criminal organisations and Colombia's most-wanted fugitive.
The Colombian farmer's son who became the world's seventh-richest man with his ruthless dominance of the global cocaine trade was hunted for years before police killed him in his hometown of Medellin in 1993.
Over the years, thousands of people were killed in violence unleashed by his Medellin cartel.
He has recently inspired several films and series including "Narcos," a hit on Netflix which is in its second season.