<p>Over the past few decades, the rising prevalence of metabolic dysfunction-associated steatotic liver disease has paralleled the global rise in living standards. It is a progressive disease and may advance to liver fibrosis, cirrhosis, and hepatocellular carcinoma. These stages often necessitate liver transplantation. At present, resmetirom and semaglutide are the only two drugs approved by the US Food and Drug Administration for the treatment of metabolic dysfunction-associated steatohepatitis. Therefore a comprehensive evaluation of their adverse events, efficacy, cost-effectiveness, social acceptance, and accessibility remains necessary. Adenosine monophosphate-activated protein kinase (AMPK) regulates the pathophysiological progression of this metabolic liver disease by controlling phosphorylation. As such, targeting AMPK represents a promising therapeutic strategy. Natural products offer advantages, including structural diversity, low toxicity, and multi-target effects. This review synthesizes current evidence on the therapeutic potential of natural products in metabolic dysfunction-associated steatotic liver disease. It focuses on AMPK-mediated mechanisms involving key regulators, such as acetyl-CoA carboxylase, sterol regulatory element binding protein-1C, peroxisome proliferator-activated receptor alpha, the liver kinase B1/AMPK/sirtuin 1 cascade, mechanistic target of rapamycin, nuclear factor kappa B, and nuclear factor erythroid 2-related factor 2.</p> Graphical Abstract <p></p>