Eleven cars of the 98-car southbound Norfolk Southern train carrying mixed freight derailed, and several cars caught fire, WCMH-TV, Columbus, reported.
Neither the number of train cars that caught fire nor the cause of the derailment was known, officials said.
About 100 people living near the derailment were evacuated to the fairgrounds.
Fire officials told WCMH 20,000 gallons of ethanol were burning.
Officials said several cars contained styrene which, if ignited, can emit a gas that affects the nervous system if inhaled, becoming a "nerve agent." Those cars weren't involved in the derailment or fire.
Two people in the vicinity of the train when it derailed were injured and drove themselves to a nearby hospital, officials said.
No train personnel were injured, Norfolk Southern said.
Officials said they would hoped to extinguish the fire by midday and allow evacuees to return to their homes. Police, fire and hazardous materials personnel were at the scene.
"Hopefully by the end of the day they [those who were evacuated] will be back in their homes," Assistant Chief Dave Whiting of the Columbus Fire Division told The Columbus Dispatch.
The National Transportation Safety Board said investigators were dispatched to the scene. The federal agency said railroad investigator Cy Gura would lead the investigation.
The Central Ohio Transit Authority said 135 to 140 buses that operate out of a garage near the derailment would not be in use until further notice, WCMH-TV said.
Witnesses said the derailment triggered an explosion and fireball visible from miles away.
"The heat was so intense it was suffocating," Nicholas Goodrich, 35, who ran to the scene, told the Dispatch. "It felt like it was 400 degrees. The heat was shaking me, like wind was blowing."