<p>Adenosine monophosphate-activated protein kinase (AMPK) is a conserved serine/threonine kinase that acts as a central regulator of cellular energy homeostasis. Activated by an elevated AMP/ATP or ADP/ATP ratio under energy-depleting conditions such as exercise, caloric restriction, or hypoxia, AMPK shifts cellular metabolism by promoting catabolic pathways (e.g., fatty acid oxidation, autophagy) and inhibiting anabolic processes (e.g., lipid and protein synthesis) to restore energy balance. Beyond its classical metabolic role, AMPK also influences epigenetic regulation, mitochondrial biogenesis, and oxidative stress responses—key components implicated in metabolic memory, a phenomenon where transient hyperglycemia induces lasting cellular dysfunction. This persistent “memory” contributes to chronic diabetic complications, including nephropathy, retinopathy, cardiomyopathy, and impaired wound healing. AMPK activation has been shown to mitigate these effects by inhibiting NF-κB-driven inflammation, enhancing SIRT1-PGC-1α-mediated mitochondrial function, and reversing hyperglycemia-induced histone modifications and DNA methylation. Both synthetic activators (e.g., metformin, AICAR, A769662) and natural compounds (e.g., resveratrol, berberine, curcumin) have demonstrated the ability to restore metabolic balance and improve insulin sensitivity in preclinical models. However, challenges persist regarding the long-term safety, bioavailability, and tissue specificity of these agents. This review explores the multifaceted roles of AMPK in metabolic regulation and its emerging therapeutic potential in countering metabolic memory. A deeper understanding of AMPK signaling pathways may enable the development of targeted interventions to prevent or reverse the long-term complications of diabetes and other metabolic disorders.</p> Graphical abstract <p></p>