This snake occurs in a wide range of aquatic and wetland habitats: swamps, sloughs, delta bayous, bayheads, ponds and streams in pine flatwoods, pine-palmetto forest, offshore keys, marshes, river bottoms, lowland floodplains, tidal stream courses, dune and beach areas, clear upland brooks, drainage ditches in some southern cities, brackish waters, and sometimes salt marshes (Ernst and Ernst 2003, Campbell and Lamar 2004). Cottonmouths may aggregate under waterbird rookeries. Hibernation sites include rocky wooded hillsides, in crayfish burrows, under rotting stumps or other cover, or in burrows of mammals (e.g., beavers, muskrats) or tortoises.

This species is endemic to the United States. It range extends from southeastern Virginia (near junction of Appomattox and James rivers) to southern Florida, west to central Texas, Oklahoma, Arkansas, Missouri, and southeastern Kansas (Triplett, 1991, Herpetological Review 22: 135), and north in the middle Mississippi River drainage to southern Illinois (Mitchell 1994, Phillips et al. 1999, Werler and Dixon 2000, Minton 2001, Campbell and Lamar 2004).

Many occurrences are protected in state parks, national parks, wildlife refuges, and national forests.