Along the IL side starting on the north end -
Galena is an old town, President Grant lived and worked there. Main street full of little shops and restaurants.
Savannah has a Poopy's. Definitely a unique bar and restaurant.
In Rock Island (Quad Cities) is John Deere HQ with a good museum. Also the Rock Island Arsenal has a good museum and national cemetery.
For quaint - At Oquawka is the grave of Norma Jean Elephant, a circus elephant that was struck and killed by lightning, then left laying when the circus left town. Her grave is across from the courthouse. Wile in Oquawka go to any of the bar/restaurant for fresh fish.
Nauvoo is an interesting little town with a very nice state park/campground. It was settled by the Mormons (Latter Day Saints) in the early 1800s. The old Mormon settlement has been restored which includes the homes and businesses of many of the original Mormon people, such as Joseph Smith, founder of the Mormon Church, and John Browning the gun maker. Also is the Mormon Temple rebuilt as it was in the early 1800s. Quite impressive site both in size and appearance particularly when one considers when it was originally built. At one time Nauvoo was one of the largest cities in IL. At that time states and even individuals could assemble an army. The Mormon Army was the 4th largest in the US. After Joseph Smith was killed the Mormons moved west and settled at Salt Lake City. Joseph Smith is buried at Nauvoo.
From Nauvoo make a side trip to Carthage, IL. In 1844 Joseph Smith, founder of the Mormon Church and his brother Hyrum, were being held in the Carthage jail when a mob broke into the jail and shot and killed both men.
On south of Nauvoo is Quincy, IL and then Hannibal, MO. Hannibal is famous for Mark Twain and the town has quite a few attractions about Twain's time in Hannibal. South of Hannibal is the Mark Twain Cave which Mark Twain wrote about in his books.
Staying on IL 96 south into Calhoun County is a peaceful drive. You'll go thru Kampsville which has several major archeological sites of very early Native American settlements. You can cross the Illinois River in Kampsville on the free state operated ferry but I suggest you continue south on IL 96 thru Hardin.
At Hardin is a nice little restaurant (Mel's Riverdock) noted for their homemade pies. They're hard to resist but I recommend waiting to eat for just another few miles.
Take the Brussels Blacktop south out of Hardin to Brussels. For a really great meal stop at the Wittmond Hotel in Brussels. They only have 1 thing on the menu but it comes with a lot. It's served family style. The first course will be sausages, beef, fruits, vegetables (cooked and uncooked), breads. All you can eat but don't fill up because the 2nd course is larger. Fried chicken, mashed potatoes, vegetables, jams, jellies. If you can clean the server then ask for more. All the food is locally raised, grown, made and prepared. Best $15 meal you'll ever have.
South of Brussels you end at the Brussels Ferry which is a free state operated ferry that takes you to just north of Grafton. If you turn left (north) off the ferry you will go to the Pere Marquette State Park. Very nice campground on the river. If you turn right off the ferry then you go into Grafton.
Grafton has a lot of shops, restaurants, bars, wineries, and tourist spots. Very popular during the summer particularly during the weekend. The Loading Dock is on the south side of Grafton located on the Mississippi River. A nice place to sit on the deck, have a cool drink, and watch the river traffic.
South of Grafton is Alton. A lot of historical sites which you can find on line or at the visitor center in town. Alton IL is where Lewis and Clark camped and supplied before jumping off on their expedition 1804.
After Alton you might want to jump on I-255 and bypass the metro east area. It's heavy industry and some areas which aren't the best or safest to travel, ie, E St Louis. Take I-255 to IL 3 which continues on south.
However, one spot along this path well worth visiting is Cahokia Mounds Historic Site. It is believed that at one time it was the largest settlement along the Mississippi River and possibly North America outside of the pre-Columbian settlements in Mexico. There are over 100 manmade mounds on site. The largest is Monks Mound is the largest earthen structure in the US. It was abandoned about 1300.
At Chester IL make a quick stop to visit the Popeye sites. The author of Popeye was from Chester and there are the usual statues, etc to the Popeye characters. Also while in Chester just take a drive past Menard State Pen. Quite a site.
Leaving Chester you can continue on IL 3 or make a short drive east to Carbondale and take IL 127 south. You'll end up at the same place but I think IL 127 is a nicer, prettier drive. Carbondale is home to Southern IL University.
Eventually you end up in Cairo IL. Cairo has a lot of historical significance but unfortunately it is just a shell of the city it use to be. South of Cairo at the very southern tip of IL where the Mississippi and Ohio Rivers meet is Ft Defiance State Park.
After leaving IL you can cross into either MO or KY. You'll be entering the New Madrid earthquake area. You can research that and read about the New Madrid Earthquake of 1811-1812 which magnitude was so large that the Mississippi River ran backwards, Reelfoot Lake was created, and church bells rang in Boston 1000 miles away. For 3 months the area experienced numerous 7-8 magnitude earthquakes.
When traveling thru Sikeston, MO be sure to stop at Lambert's Restaurant "Home of the Throwd Rolls". Really good food and huge hot rolls actually thrown at you. Whatever you order will be an extremely large serving and then they bring the 'pass arounds' of fried okra (really good), green beans, sorghum for the rolls, etc.
Each of the little towns on both sides of the Mississippi on into Memphis have unique shops and stories to tell.
