Spend your first night in Memphis at the Madison (from $175), an infinitely cooler alternative to the overhyped Peabody, with contemporary furniture, bold splashes of color, and a fitness center and lap pool built into an old bank vault.
From Memphis, head south on Route 61, then east on Route 49 (about 135 miles total) to Greenwood, Mississippi, where the Alluvian (from $185) is a welcome anomaly: a sumptuous, $10 million, 50-room boutique hotel in a sleepy little town, once the cotton capital of the world.
Three hours south, in Natchez, Mississippi, check into the Monmouth Plantation (from $195), a Greek-revival-style mansion outfitted with wireless Internet, working fireplaces, and Jacuzzi tubs. A more intimate alternative is the Joseph Newman Stone House (from $110), originally a billiard hall built around 1850.
Take the slower but more scenic Route 61 to New Orleans and stay at the Soniat House (from $245), where each of the 32 rooms and suites are turned out with antique furnishings and art on loan from the New Orleans Museum of Art. Ask for Room 21 if you want soaring ceilings and views of Chartres Street, or Room 32 for a private terrace.