Food intoxications by pufferfishes have been reported all over the world producing several deaths every year and toxicological profiling of various species of pufferfishes is crucial to avoid potential health hazards imposed by ingestion of them. The present study is focussed to assess the toxicity of the pufferfish Takifugu oblongus, from the coast of Tamil Nadu, India, in different seasons. The toxicity was evaluated by mouse bioassay using Swiss Albino mice which is expressed in mouse units (MU/g). Anatomical changes were observed which is followed by histopathology of the dead mice tissues to prove the toxicity. The toxicity of liver was at its maximum during the pre-monsoon season with 163 MU/g and skin showed least toxicity with 75.88 MU/g. Post-monsoon season results showed that gonads proved maximum toxicity with 249.06 MU/g, while skin showed lowest toxicity with 89.34 MU/g. Histopathology analysis of the dead mice showed various inflammations and degenerations in the brain, heart, liver and kidneys. The toxicity of the pufferfish followed a seasonal pattern differing in various seasons. The present study evidently proved that T. oblongus is highly toxic and consumption of the same can pose serious dangers of health hazards and possibility of lethality to humans. © 2017 Indumathi S M and Samanta Sekhar Khora.