Introduction: Methamphetamine (Meth) is a highly addictive psychostimulant and induces neuroinflammatory responses. Melatonin is a neurohormone that has protective effects and reduces inflammation in the central nervous system. Our study focused on the melatonin effect on memory impairment, NLRP3/IL-1β axis, and gasdermin D and caspase-1 expression in the hippocampus of a rat model of Meth use. Methods: Meth and melatonin were administered to the rats for 21 consecutive days. The memory was evaluated using alternation behavior in Y-maze. NLRP3 and IL-1β were assessed by western blotting and ELISA, respectively. Gasdermin D and caspase-1 expression levels were evaluated using qRT-PCR. Results: The NLRP3 and IL-1β were elevated in the hippocampus following Meth injection. Moreover, Meth increased gasdermin D and caspase-1 expression levels. After 21 days of Meth use, memory impairment was seen in the Y-maze test. Melatonin significantly improved memory and decreased the expression of NLRP3, IL-1β, gasdermin D, and caspase-1 in the hippocampus. Conclusion: Our study revealed that inflammasome formation and pyroptosis pathway are involved in Meth-induced neurotoxicity. Melatonin may be a potential treatment against neurotoxicity and cognitive disorders caused by Meth.