Annona muricata (AM) is a herb traditionally used to treat various human ailments. The mechanistic effect of Annona muricata extract on NALP3 inflammasome activation is not well understood. Objective: The present study investigates the inhibitory effects of Annona muricata extract on NALP3 inflammasome activation and its role in sepsis prevention. Methods: Sepsis was induced in mice by intraperitoneal injection of Escherichia fergusonii. Mice were treated with Annona muricata extract. Its effect on liver was assessed both histologically and biochemically. Lipid peroxidation, level of IL-1β, TNF-α was measured colorimetrically and using Elisa kit in liver homogenates. The expression levels of IL-1β, TNF-α, caspase-1 and NALP3 genes were measured using RT-PCR. Results: AM extract significantly minimized the inflammation by decreasing the level and the expression levels of IL-1β and TNF-α in a time-dependent manner. Significant decrease in the gene expression level of caspase-1 and NALP3 was observed. Histopathologically, normal architecture of the liver of infected mice was regained after the herb treatment. Conclusion: Anonna Muricata can act as a potent therapeutic agent in treating various NALP3 associated inflammatory disorders.