Four women and two men were killed, and at least 100 people are injured in the town of just over 9,000. Earlier reports from local officials incorrectly said 10 died in the predawn storm.
About 300 homes and businesses received damage from the storm. The mayor of that town says the damage is devastating.
"We can deal with floods, we can deal lots of other things, but dealing with a tornado like this is heartbreaking," said Harrisburg Mayor Eric Gregg.
Illinois Governor Pat Quinn is in the small downstate community to survey the damage done and has declared it a disaster area. Harrisburg is about 330 miles from Chicago.
Rescue crews from as far away as Carbondale and Champaign are taking part in house to house searches.
Governor Quinn's disaster declaration will make recovery resources available to affected areas of Saline County.
Storms also pounded other parts of the Midwest, including Branson, Missouri.
Anyone looking to check on loved ones in the area can log on to RedCross.org and register at Safe and Well.
The National Weather Service says the twister that roared through Harrisburg just before 5 a.m. was an EF4 with top winds of 170 mph. At its worst, the tornado was more than 200 yards wide. The meteorologist in charge of the local NWS office began issuing alerts to local authorities about 27 minutes before the twister touched down in Harrisburg. The local hospital had enough warning to move all its patients into interior rooms.
Hundreds of homes have been damaged or destroyed.
Harrisburg's mayor says his city will rebuild following the deadly tornado. In the meantime, a curfew will be in place Wednesday night starting at 6 p.m.
"Our hearts are broken right now," Gregg said. "We are trying to make sure every man, woman and child is accounted for in our community. We are trying to take care of those that have been displaced and whose homes have been devastated. So we're trying to make sure we're taking care of what we can at the moment. And I am thankful. I want to say thank you to the communities that have come to our rescue today, because it speaks well to those in Illinois. I am grateful and thankful for that."
Gregg said he awoke when the sirens went off and went outside. He lives on a hill and said he had a good vantage point of the town.
"It was eerily quiet when the sirens were blasting. I just had this bad feeling. I left home and had the radio going, and once I found out the path was on-site 15-20 minutes after it went through, driving around the community as mayor, you care about every man, woman and child and it breaks your heart to see this kind of destruction in our community," Gregg said. "It's an act of God and something you try to prepare for and deal with, but I don't know when we would ever be fully prepared for something like that. It's when people are sleeping, and they don't have the televisions and things on. So, they don't get the warning."