Up the Mississippi from New Orleans to St. Louis
I would definitely stop in Natchez and spend a day touring the plantation homes there. Monmouth is an oustanding place for the night. The dining room there is superb. I would also check out The Carriage House Restaurant at Stanton Hall for a wonderful lunch.
In Vicksburg you could tour the old antebellum homes and the Vicksburg National Military Park.
Have lunch/dinner @ Rusty's River Front Grill @ 901 South Washington St., Vicksburg, MS 601 - 638 -2030.
or @ Walnut Hills @ 1214 Adams Street, Vicksburg, MS 601 - 638 - 4910 for southern cooking.
Stop in Greenville, MS if you have time for dinner at Doe's Eat Place @ 502 Nelson Street
Greenville, MS 662 - 334 - 3315.
If you have time venture East to Greenwood and spend a night at the lovely Alluvian Hotel mentioned by DCBBQ below. Have lunch at Crystal Grill and dinner at Lusco's or Giardinia's in the hotel. KC's in Cleveland is closed for good. In Clarksdale there's the Blues Museum as well as good dining at Ground Zero, Abe's BBQ and Madidi's.
Just an hour or so East of Clarksdale is the great City of Oxford home of The University of Mississippi, William Faulkner and many fine restaurants including City Grocery, Big Bad Breakfast, The Snack Shop, Downtown Grill, Prime, Ajax and many others.
Bon Appetit and have a safe trip.
You definitely need to have tamales while in the Delta (which runs from the steps of the Peabody Hotel in Memphis to the dock in Vicksburg). Google Mississippi Hot Tamale Trail. The "river" tamales are much smaller and lighter than Tex-Mex tamales. they are not to be missed.
The Delta also is very good for steaks. You can combine the two for dinner at Doe's in Greenville. Make sure you ask how large the steak is. The "small" steak used to be 2 pounds (people share). Note - Doe's is at best a large hole in the wall and it is located in a neighborhood that makes some people uneasy, but it is great.
Also very good for steaks is KC's in Cleveland, which also has a suprisingly good wine list.
You may want to take a more westerly route through Greenwood, which boasts a great - repeat great -- hotel, the Alluvian, which in turn has a well-regarded high end restaurant. Also in Greewnood is Lusco's. Have the pompano. If you go through Yazoo City, try Stubb's at the US 49 split. It's a good meat and three place with very good pies. Actually, most fo the towns will have a good meat and thre place near the town square. Very few places have good sandwiches and, at the risk of starting an argument, the Delta is not where you want to get barbecue. Save that for Memphis. You should cross the river at Memphis and head north. The Dixie Pig in Blythewille is great.
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