<p>The high-fat diet (HFD)–induced hypothalamic inflammatory response is considered a common pathogenic basis for various metabolic diseases. Exercise can improve overall metabolic health, and it exerts a positive impact on local inflammation. The purpose of this systematic review was to evaluate existing evidence and analyze the effects of exercise intervention on the behavior, inflammatory factors, glial cells, and feeding neurons of animals with HFD-induced hypothalamic inflammation. We systematically searched PubMed, Scopus, Ebsco, EMBASE, and Web of Science databases from database establishment to July 2024 to identify all animal studies on exercise intervention in HFD-induced hypothalamic inflammation. Two researchers independently conducted literature screening to determine inclusion in the study. Finally, SYRCLE’s risk of bias tool for animal studies was used to assess the risk of bias in the included studies. A total of 11 studies were included. Among them, 10 studies used mice and 1 study used rabbits. Overall, the inclusion of research supported the improvement of behavior, inflammatory factors, glial cells, and feeding neurons in animals with HFD-induced hypothalamic inflammation through exercise. However, 2 studies did not find significant changes in food intake and body weight, and 4 studies found that exercise intervention reduced the expression of anti-inflammatory factors (IL- 10 and SOCS3). Different exercise programs, such as forced and voluntary exercise, may be potential reasons for the differences in outcomes. On the basis of existing evidence, exercise appeared to be a potential protective and preventive factor against HFD-induced hypothalamic inflammation. However, the inconsistent results suggest that further research is needed in the future to thoroughly elucidate the mechanisms by which exercise improves and prevents hypothalamic inflammation.</p>