Inflammation is a characteristic of obesity. The rich compounds in lemon peel have anti-inflammatory effects. This study examined whether fermented lemon peel can have an anti-obesity effect on obese mice induced by a high-fat diet (HFD) by regulating inflammation. The lemon peel fermentation supernatant (LPFS) could inhibit the weight gain of mice and improve the lesions of the liver and epididymal adipose tissue. In addition, LPFS regulates blood lipids, liver function, and inflammation-related indicators in the serum of obese mice. LPFS plays a positive role in regulating the inflammation and obesity-related genes in liver tissue and adipose tissue of obese mice. High-performance liquid chromatography showed an increase in the contents of compounds with antioxidant or/and anti-inflammatory effects and compounds with anti-obesity effects. These results suggest that the LPFS could help reduce obesity in obese mice induced by an HFD by adjusting the balance of the inflammatory response. PRACTICAL APPLICATIONS: Obesity often increases the risk of chronic diseases, and mild inflammation is a feature of obesity. Therefore, timely suppression of inflammation in the body can help control the occurrence of obesity. This study clarified the anti-obesity effect of fermented lemon peel on a high-fat diet (HFD)-induced obese mice by regulating the body's inflammatory response and confirmed that fermentation improves the anti-inflammatory activity of lemon peel. This study provides important references for future investigation, prophylaxis, and treatment of inflammation and obesity-related diseases, as well as the advances in functional foods and fermented foods with anti-inflammatory and anti-obesity activities.