It feeds on rodents, snakes, lizards, frogs, fish and the eggs and chicks of ground-nesting birds. It sometimes hunts in shallow water, though generally steers clear of deep water unless threatened. It is not a tree climber, and has the wrong claws for this activity: instead it is a powerful digger, and a specialist at excavating for beetles and other prey. Its coarse hair helps to protect it from the poison fangs of the snakes it preys on, conquering them through sheer agility.

Enemies of the large grey mongoose include larger birds of prey and the large carnivores. Family groups, consisting of both parents and their young, move in a line in head-to-tail formation, with the scent glands located near the anus helping to keep the file in formation. Unlike other mongooses, they do not seem to make use of the odour from these glands as a defensive weapon if trapped or threatened by man, using their high pitched staccato distress call instead. The large grey mongoose is more active by day than by night. It sleeps in a sitting position in a burrow or crevice.