SEMO Road Trip Series

Southern Missouri is a region most travelers pass through without ever really seeing. Beyond the interstates and tourist towns lies a landscape of Ozark ridges, winding highways, river cities, forests, farmland, and some of the most underrated driving roads in the Midwest.

This journey begins in St. Louis, where the Mississippi River, massive freeway interchanges, and the eastern terminus of Interstate 44 set the stage for a westbound run across Missouri’s historic Route 66 corridor. From the urban skyline and rolling hills around St. Louis, the route follows Interstate 44 southwest through the heart of the Ozarks toward Springfield — tracing one of America’s classic travel corridors through forests, ridgelines, and small-town Missouri.

From Springfield, the trip shifts southeast onto U.S. Route 60, crossing deep into southern Missouri through long stretches of farmland, wooded hills, and regional highway towns before reaching the forests and river country around Poplar Bluff and Cape Girardeau. Along the way, the landscape gradually transforms from Ozark highlands into the edge of the Mississippi Delta, revealing a side of Missouri many travelers never experience.

The route then turns west again along U.S. Route 160, one of the defining highways of southern Missouri, weaving through mountain towns, forest valleys, and the rugged terrain of the Ozarks. Scenic stretches of Missouri Highways 125, 76, and 14 add winding ridge roads, quiet countryside, and some of the region’s best driving scenery before reconnecting with U.S. Route 63 and heading north once more.

Designed as a long-weekend-scale adventure, this trip blends major interstates, historic U.S. highways, scenic Ozark backroads, river cities, and classic Americana into one connected journey across southern Missouri. It’s a drive built around the roads themselves — the changing landscapes, the small towns, the overlooked corridors, and the feeling of crossing an entire region one highway at a time.