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Leptin is the oldest studied adipokine, and its mechanism of action in the regulation of energy metabolism remains a hot topic of current research. In this paper, we systematically review the progress of clinical and basic research on leptin and energy metabolism from 1994 to 2026. It is shown that leptin can regulate the energy metabolism homeostasis through autocrine, paracrine and neurohumoral pathways (e.g., hypothalamic-leptin-melanocortin axis). In addition, the effects of mainstream weight loss strategies such as dietary control, pharmacological interventions and exercise on leptin levels, and their underlying mechanisms were investigated in this paper, with the aim of providing a theoretical basis for the clinical application of leptin in metabolic diseases (e.g., obesity, diabetes mellitus). Future studies need to further clarify the molecular mechanisms of leptin resistance and explore precise intervention strategies based on the leptin signaling pathway.