Here, we systematically sort out the core role of the PI3K/AKT signaling pathway in the key pathological processes involved in the progression of MASLD, including lipid metabolism, IR, inflammation, oxidative stress, etc. Given the pivotal role of the PI3K/AKT signaling pathway in the pathogenesis of MASLD/MASH, this review compiles natural compounds derived from medicinal herbs that exhibit protective effects by modulating this pathway. The gene discussed is AKT1; the disease is metabolic dysfunction-associated steatotic liver disease.