In summary, this study provided substantial experimental evidence that clopidogrel can prevent and reverse HFD-induced hepatic steatosis in mice through enhanced phosphorylation of the AMPK signaling pathway and suppression of PPARG-mediated uptake of fatty acids in the liver and primary hepatocytes of mice, suggesting that clopidogrel could be repurposed to fight MASLD for future patient care. Here, PPARG is linked to metabolic dysfunction-associated steatotic liver disease.