Sleeve gastrectomy is one of the effective interventions for severe obesity; however, long-term weight regain after surgery substantially compromises its clinical benefits. Weight regain is not attributable to a single cause, but rather represents a coordinated defensive response across multiple systems under a state of negative energy balance. This review first outlines the epidemiology and definition of weight regain following sleeve gastrectomy. On this basis, we elaborate on the underlying biological mechanisms, including the "metabolic memory" of adipocytes and immune cells, which constitutes the tissue-level susceptibility basis; the remodeling of the gut microbiota-gut-brain axis, which participates in energy absorption and reprogramming of appetite centers; the loss of lean body mass and associated metabolic adaptation, which drive weight rebound through both energy expenditure and appetite regulation; and the structural and functional alterations in hypothalamic appetite-regulatory networks, which form the neural foundation for sustained increases in food intake. These mechanisms are interconnected and collectively shift energy balance toward a positive direction. Furthermore, we propose a three-tiered stepwise management strategy-"lifestyle intensification-pharmacological intervention-endoscopic and revisional surgery"-with a focused review of the evidence and differential efficacy of GLP-1 receptor agonists and revisional surgery in managing weight regain after sleeve gastrectomy. This review aims to provide clinicians with an integrated framework spanning mechanistic understanding to stratified intervention, facilitating the transition of bariatric surgery toward a long-term chronic disease management model.