Debris was detected on radar and multiple reports of damage from around Hattiesburg and Petal suggest the tornado may have been rather strong.
Four people died after the twister blew through the city and surrounding area, Forrest County Coroner Butch Benedict said.
Mayor Johnny DuPress has signed an emergency declaration for Hattiesburg.
Search and rescue teams were deployed to Hattiesburg where downtown buildings including a fire station and portions of William Carey University were damaged.
Students at William Carey were reporting minor injuries, the university said.
According to the university's official Twitter page, authorities checked all the dormitories to make sure all students were safe. A spokesperson for the Mississippi Emergency Management Agency said the tornado touched down in Lamar, plowed through Forrest and then struck Perry before dissipating. "There is damage to most buildings on campus including cars and a home across campus is damaged". "Damage to dorms, Tatum Court, Thomas Hall", the university said on Twitter.
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Windows were blown out and roofs of buildings peeled back at the Hattiesburg Salvation Army, WDAM reported.
Interstate 59 north of Hattiesburg was closed because of debris, said the agency, which asked the public to avoid traveling in the area because of downed power lines and other destruction.
A reported tornado hit Hattiesburg, Mississippi at 3:45 a.m. EST.
It came as a band of severe weather moved across the region, and the NWS issued a tornado watch for parts of Alabama and Florida until 10 a.m. ET.
Four people were killed early Saturday when a tornado ripped through the area.