The detrimental effects of organophosphate (OP) nerve agents have been reported but the mechanisms mediating these multiple effects are not well understood. Recent use of nerve agents in Syria and the UK illustrate their continuous threat to the modern world. Epigenetic and autophagy studies are useful to address the issues related to regulation of gene and protein expression by which nerve agents could impact on human health. These studies help to understand molecular mechanisms underlying the multiple neurotoxic effects of nerve agents. In the present study, changes in epigenetic (global DNA methylation and histone acetylation) and autophagic marker proteins were studied in the nerve agent sensitive rat brain areas (piriform cortex and hippocampus) after soman (1xLD50) exposure. Global DNA methylation analysis revealed that nerve agent induced hypomethylation in the brain regions at 1 and 7 days post exposure. In contrast, DNA hypermethylation was observed at 30 days post soman exposure, demonstrating a possible compensatory mechanism. Western blot analysis showed significant increase in the histone acetylation levels after soman exposure in the piriform cortex and hippocampus. The present study observed the changes in autophagic proteins of nerve agent poisoning for the first time to the best of our knowledge. Immunoreactivity levels of autophagic proteins (LC3-II, ATG-5 and p62) were transiently increased in the rat piriform cortex and hippocampus after soman exposure. In conclusion, this study provides insight into the epigenetic and autophagic changes in the brain following soman exposure and their possible role in the neuronal damage and development of multiple neurological effects.