“Please join me in praying for the victims of the explosion in Texas and their families," he said on the English channel of his Twitter account, which uses the handle @Pontifex.
Between five and 15 people are believed to be dead and 160 injured in the explosion that took place Wednesday night near Waco, Texas.
Emergency services and rescue workers are still searching through smoldering ruins for missing firefighters and survivors of the huge blast.
The explosion happened at a fertilizer company just off the town of West, a small community of 2,300 people just 20 miles north of Waco.
First-responders were able to evacuate 133 residents of the West Rest Haven Nursing Home, some in wheelchairs, since they were at the plant fighting a fire, about 30 minutes before the deadly blast.
Authorities say 75 houses, several businesses and a 50-unit apartment complex were damaged.
Experts say it is possible that the highly explosive chemical ammonium nitrate, which can be used to make fertilizer, was being stored at the plant.
The U.S. Chemical Safety Board said it was sending a large team to investigate the incident.
The Pope has previously launched appeals at his weekly general audience and during his Sunday Angelus where thousands of pilgrims gather.
But his Dec. 12, 2012 Twitter debut gave the pontiff another venue for making his prayer requests or calls for peace when violence breaks out.
The account shows 18 posts since Pope Francis became the Successor of Peter on March 13, 2012.
Pope Francis tweeted a prayer request for the victims of a fertilizer plant explosion in Texas.
Disasters, Pope Francis