There were no firm casualty figures, but deaths were reported. Dozens of people were reported missing.
Numerous funnel clouds were reported.
"This is an enormous outbreak that's going on right now across Kentucky and the South," National Weather Service meteorologist John Gordon told CNN. "It's crazy. It's just nuts right here."
Storms stretched from Missouri to South Carolina, some battering towns with hail the size of baseballs, AccuWeather.com reported. Tornado watches were issued for southeastern Missouri, southern and central Illinois and Indiana and western Kentucky.
Back-to-back storms hit Henryville, Ind., turning buildings to toothpicks, aerial video showed. Twisters as wide as three football fields tore through the area.
Maj. Chuck Adams of the Clark County Sheriff's Department said the town of Marysville, Ind., is "completely gone," AccuWeather.com reported. In Henryville, local reports said the high school had been damaged. It was unclear whether anyone was trapped in the wreckage.
Severe thunderstorms stretched from central Indiana and Kentucky north and east. Another line of storms stretched from western and central Tennessee south to Louisiana, Mississippi and Alabama.
"We are trying to gather info from across the state from ambulance crews and hospitals at this time. Reports of injuries are coming in and we are trying to confirm them," said Dean Foener, a spokesman for the Tennessee Emergency Management Agency.
The storms pulled down power lines, affecting thousands of customers.
Tornadoes and other storms in parts of Alabama Friday snapped power lines, damaged property and prompted school officials to end classes early.
Officials said several storm-related injuries were reported, but no deaths, The Huntsville Times reported.
Emergency officials said a rain-wrapped tornado was sighted in the Harvest area and power was out in several areas, the Times reported.
Emergency Management Agency personnel in Limestone County reported two tornadoes touched down one on top of another, but there were no early reports of damage.
Severe weather in northern Madison County knocked down power lines and felled trees, officials said
The Birmingham News reported several school systems across the state closed early because of the threat of severe weather.
Storms also brought the potential for tornadoes to the Ohio and Tennessee valleys Friday, AccuWeather.com reported.
Severe weather slammed an area extending from Missouri into South Carolina with big chunks of hail, some reported as baseball-sized.
Meteorologists reported St. Louis was hit by hail that measured about a half inch in diameter. In Nashville, hail was described as nickel-sized.
Southeastern Missouri, southern and central Illinois, central and southern Indiana and western Kentucky were under a Potentially Dangerous Situation Tornado Watch issued by the National Weather Service, which said it issues only a handful of that type of watch during a year.
Lines of severe storms cascaded from northern Alabama through central and eastern Tennessee and into Kentucky, forecasters said.
"If you get hit by one storm, you can get hit by another," AccuWeather.com Expert Senior Meteorologist Alex Sosnowski said.
The area is part of a multistate region reporting at least 30 tornadoes responsible for 13 deaths Wednesday, from Nebraska and Kansas across southern Missouri to Illinois and Kentucky.
Six people were killed in Harrisburg, Ill., about 55 miles southwest of Evansville, Ind., when a house lifted up by a 170 mph tornado fell on them and crushed them. Three people were killed in southern Missouri, three in eastern Tennessee and one in northeastern Kansas.
A tornado, with winds of 111 mph to 135 mph, caused significant damage and dozens of injuries in the country music resort city of Branson, Mo. The city's waterfront area, 15 hotels and at least six signature theaters sustained extensive damage, officials said.
President Barack Obama spoke Thursday with the governors of Missouri, Illinois, Kentucky, Indiana, Tennessee and Kansas "to offer condolences" and federal help, the White House said.
Illinois Gov. Pat Quinn was the first state leader to ask for assistance in damage assessment, a customary step before formally requesting federal aid.