Two crew members were treated for minor injuries in the 4:15 a.m. collision at a crossing near Citra, about 25 miles north of Ocala, CSX spokeswoman Kristin Seay said.
One of the trains was carrying nonhazardous phosphate rock; the second was transporting coal, Seay said.
CSX is trying to determine if fuel was released from the locomotives and has sent environmental crews to contain any possible spill.
The cause of the crash has not been determined, but CSX is investigating.
The sheriff's office said some 20 cars derailed. CSX said it's working to determine how many cars were involved.
The phosphate train was traveling from Mulberry, Florida, to Chicago with three locomotives and 100 loaded phosphate cars, CSX said. The coal train was going from Pembroke, Kentucky, to Tampa with three locomotives and 110 loaded cars of coal.
CNN's Shawn Nottingham contributed to this report.