This large rattlesnake is found along the Atlantic and Gulf coasts of the southeastern US. It is an inhabitant of typically open or low-canopy environments, such as longleaf pine savannas, sandhills, xeric scrublands, coastal dunes, marsh hammocks and fringes/clearings in maritime forests. Its camouflage is optimized to blend into grasses and vine cover, where it waits in ambush for prey. This species is a rabbit-specialist, but will take squirrels and cotton rats when the opportunity arises.

Its venom is primarily hemotoxic, with a small but effective fraction of myotoxicity which causes quick, intense muscle shutdown in the hind legs of small mammals. This gives its venom a level of "redundancy", where the hemotoxin and myotoxin are both aimed to incapacitate or "drop" a fleeing prey (think sprinting rabbit). If one should fail to stop the heart/hind legs, the other is still likely to succeed, better ensuring the strike will not go to waste against a target which flees far enough before dying.

Eastern diamondbacks use gopher tortoise (Gopherus polyphemus) burrows to over-winter. The destruction of tortoise burrows and the declines of gopher tortoise populations directly threatens inland populations of this species. Populations on the coast are subject to losing foraging habitat (coastal sand dunes & marsh edge) to development as builders quickly carve up waterfront property. Other threats include fire suppression, which causes open pinewoods and scrublands to close up into thick hardwood forests; and intense human persecution. While almost all "rattlesnake round-ups" in the eastern US are defunct or converted to wildlife festivals, the damage has already been done in many localities.

This species is the largest of any rattlesnake, coming in at just under 8ft (242cm) in length and over 3kg (5lbs) in weight. Despite its large size, eastern diamondbacks are extremely cryptic and hard to spot when hiding from predators and/or prey.