Two of the reported twisters touched down in northeast Alabama, where residents were assessing damage to a high school, prison and other locales.
There was no immediate word on damage, or possible casualties, from that touchdown in Posey County, near the Ohio River.
Meanwhile in Tennessee, severe weather was responsible for critical injuries of as many as eight people in the cities of Harrison and Oolteweh, officials there said.
There were no immediate reports of injuries at either Buckhorn High School in Madison County or the Limestone County Correctional Facility in an adjacent county.
But there was widespread damage in Madison County, the National Weather Service said, and some injuries were reported, according to a local ambulance service.
The storm brought golf-ball-size hail, strong winds and rain into the two northeast Alabama counties before continuing on a northeastward path into Tennessee.
"We obviously have lots of debris, homes with roof damage, streets that are impassable that we have crews cutting down trees with chainsaws in order to get emergency vehicles through and as of now our crews are just going door to door on foot," said Amy Maxwell, Hamilton County, Tennessee, emergency management spokeswoman.
Between six and eight people were critically injured, and 10 others had minor injuries, she said.
The Madison County Emergency Management Agency confirmed that a rain-wrapped tornado was spotted near the Harvest area, just northwest of Huntsville, which itself was hit hard by a tornado last year.
"The key thing that let me know it was serious was the loud wind," said Hovet Dixon of Harvey, Alabama. "It almost seemed like it was trying to lift my roof off."
The scene after the storm passed in the areas where the apparent tornadoes touched down looked similar to what parts of the Midwest and South suffered earlier this week, with damaged homes and downed power lines. Thousands were without power.
The warden for the Limestone Correctional Facility, Dorothy Goode, said the prison was hit by the storm. All prisoners -- the facility holds about 2,200 -- were accounted for, she said.
These were the first reported twisters from a storm system that threatened the already hard-hit Midwest and South.
Forecasters said the areas most at risk for twisters on Friday were southern Indiana, southern Ohio, most of Kentucky, central Tennessee, northeastern Mississippi and northwestern Alabama.
Storms were expected to proliferate during the afternoon, with the most likely window for tornadoes between 4 and 8 p.m. ET, according to CNN meteorologist Sean Morris.
There is the potential for widespread damaging wind gusts, large hail and violent tornadoes in some areas.
Storms will begin to weaken during the late evening as they move east toward the Appalachians. The severe weather threat will diminish overnight Friday into Saturday morning, Morris said.
The first tornado outbreak of the week began Tuesday night and left 13 dead across Kansas, Missouri, Illinois and Tennessee, and battered parts of Kentucky as well.
National Guard troops helped police and sheriff's deputies direct traffic and patrol streets in stricken areas of Missouri and Kentucky, while those who survived began the task of cleaning up.
Four women and two men died in Harrisburg, Illinois, about 30 miles north of the Kentucky border. The tornado that struck it had a preliminary rating of EF4, the second most powerful on the rating scale, according to the National Weather Service.
The twister appeared to have been on the ground for several miles, said Harrisburg Mayor Eric Gregg, and the path of destruction was about three or four football fields wide. Sheriff's deputies said about 100 people were injured, and between 250 and 300 houses were damaged or destroyed.
One person died in each of three towns in southern Missouri where the twisters struck -- Buffalo, Puxico and Cassville -- while another three died in two east-central Tennessee counties, authorities in those states reported.
A smaller tornado caused significant damage in the music resort city of Branson, Missouri.
An EF2 tornado smashed at least seven miles of the city's commercial strip, leaving 33 people hurt, most with minor to moderate injuries.
The city's convention center and an attached Hilton were damaged, as was a portion of Branson Landing, a large shopping and entertainment complex.
City Administrator Dean Kruithof said about five or six of the city's roughly 40 theaters were damaged.
Two tornadoes were confirmed in Tennessee's Cumberland and DeKalb counties, between Nashville and Knoxville. The one that struck Cumberland County, where two people died, was an EF2 with top winds of around 125 mph, the weather service reported Thursday evening. The remaining fatality was from an EF1 twister with top winds around 90 mph, according to forecasters.