Schistosomiasis is an inflammatory disease that occurs when schistosome species eggs are deposited in the liver, resulting in fibrosis and portal hypertension. Schistosomes can interact with host inflammasomes to elicit host immune responses, leading to mitochondrial damage, generation of high levels of reactive oxygen species (ROS) and activation of apoptosis during inflammation. This study aims to examine whether ROS and NF-κB (p65) expression elicited other types of inflammasome activation in Schistosoma mansoni-infected mouse livers. We examine the relationship between inflammasome activation, mitochondrial damage and ROS production in mouse livers infected with S. mansoni. We demonstrate a significant release of ROS and superoxides and increased NF-κB (p65) in S. mansoni-infected mouse livers. Moreover, activation of the NLRP3 and AIM2 inflammasomes was triggered by S. mansoni infection. Stimulation of HuH-7 hepatocellular carcinoma cells with soluble egg antigen induced activation of the AIM2 inflammasome pathway. In this study, we demonstrate that S. mansoni infection promotes both NLRP3 and AIM2 inflammasome activation.