Evidence from pediatric studies show that infants and children are at risk for early exposure to microcystin. The present report tests the hypothesis that early life exposure to microcystin (MC), a principal component of harmful algal blooms followed by a juvenile exposure to high-fat diet feeding potentiate the development of nonalcoholic fatty liver disease phenotype in adulthood. Results showed classical symptoms of early NAFLD linked inflammation. Cytokines and chemokines such as CD68, IL-1β, MCP-1, and TNF-α, as well as α-SMA were increased in the groups that were exposed to MC-LR with the high-fat diet compared to the vehicle group. Also, mechanistically, NLRP3 KO mice showed a significant decrease in the inflammation and NAFLD phenotype and resisted the metabolic changes such as insulin resistance and glucose metabolism in the liver. The data suggested that MC-LR exposure and subsequent NLRP3 inflammasome activation in childhood could impact liver health in juveniles.