Snakebite is a ‘neglected tropical disease’ that majorly affects the rural populations in developing countries. India bears the brunt of snakebites with over 46,000 deaths and 140,000 disabilities, annually. A significant number of these bites are attributed to the widely distributed ‘big four’ snakes, namely spectacled cobra (Naja naja), common krait (Bungarus caeruleus), Russell’s viper (Daboia russelii), and saw-scaled viper (Echis carinatus). The commercial antivenoms marketed in India are only manufactured against these four species, while neglecting many other medically relevant snakes with restricted geographic distribution. Snakebite pathology is dependent on the venom composition of the population/species, which can, in turn, vary intra- and inter-specifically. Though this variation severely limits the cross-population/species antivenom efficacy, envenomations by the neglected snakes in India are treated with the ‘big four’ antivenom. Therefore, to unravel the underlying venom variability, we investigated venom proteomic, biochemical/pharmacological and toxicity profiles of the major neglected Indian snakes and their ‘big four’ relatives. To assess the effectiveness of the ‘big four’ antivenom in treating bites from these neglected snakes, we performed preclinical experiments, which revealed alarming inadequacies of the commercial antivenoms. Our findings accentuate the compelling necessity for the innovation of highly efficacious next-generation snakebite therapy in India.