The Eastern indigo snake requires large amounts of undeveloped land. Currently, the largest threat to the Eastern indigo snake is loss of habitat due to construction of buildings and roads. As development increases, habitats become fragmented and can lead to the isolation of populations or leave individuals without mates. Vehicles hit and kill Eastern indigo snakes as they cross roads within their home ranges or as they warm themselves on the pavement. Other detrimental effects associated with development include an increase in the amount of pesticides used by land owners and an increase of pets.
Pesticides can accumulate in their tissues and cause ulcers, reproductive failure, and even death.
Free-ranging or feral cats and dogs harass or even kill indigo snakes and other species of wildlife. Historically, indigo snakes were commonly killed during rattlesnake roundups, when rattlesnakes were collected from burrows and holes after gasoline was poured in burrows. This method of snake collection is now illegal in Florida, but may still occur. Indigo snakes were once heavily collected for the pet trade because of their beauty and docile temperament in captivity. It is now illegal to keep indigo snakes without a permit.