The town has an unusual name derivation: A local creek was notorious for trapping cattle in bogs, and local Native American skinners killed the wild cattle that got stuck there and salvaged the hides. The creek took its name from the Spanish word for rawhides—cuero (KWER-o). When the town was founded in 1873, it took the name of the creek. Once a round-up point on the Chisholm Trail, the town was a true "Wild West" outpost. Many Indianola residents moved inland to Cuero after devastating hurricanes in 1875 and 1886.

Today, many historic buildings remain, with more than 50 structures and homes listed as recorded Texas historic landmarks or in the National Register of Historic Places. Contact the Chamber of Commerce for driving tour information.

Cuero is the seat of DeWitt County, which was designated the "Wildflower Capital of Texas" by the Texas Legislature. Maps with routes for the best wildflower viewing are available each April from the chamber of commerce.

The Guadalupe River offers fishing and river paddling opportunities, with three official put-in sites on a Texas Paddling Trail. Cuero also is on the Great Texas Coastal Birding Trail.

Events include the Texas River Marathon and the Turkeyfest Celebration on the second full weekend of October.