ABSTRACT The sustainable utilization of agricultural by‐products presents an innovative solution to environmental and health challenges. This study proposes the upcycling of oriental melon ( Cucumis melo var. makuwa ) stems, typically discarded agricultural waste, into a bioactive extract with functional potential. The ethanol extract was evaluated for its effects on high‐fat diet (HFD)‐induced obesity and metabolic dysfunction‐associated steatotic liver disease (MASLD). CMSE treatment significantly reduced body weight and fat mass in HFD‐induced obese mice by enhancing energy expenditure, independent of calorie intake. It also ameliorated hepatic steatosis, reducing liver weight and fat accumulation while lowering serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, markers of liver function. CMSE contributed to the stimulation of thermogenesis and energy dissipation in brown adipose tissue (BAT) by increasing the expression of thermogenic genes ( Ucp‐1 and Ucp‐3 ) and elevating uncoupling protein 1 (UCP‐1) protein levels. LC‐MS analysis identified bioactive compounds, including soyacerebroside I, which is known for its anti‐inflammatory properties and may contribute to the observed metabolic improvements. However, further studies are required to validate this potential association. This study underscores the valorization of agricultural waste, transforming CMSE into a high‐value functional ingredient that supports both metabolic health and environmental sustainability. By aligning with circular economy principles, CMSE offers a dual advantage: contributing to addressing global health concerns such as obesity and liver disease while reducing agricultural waste. These findings suggest the potential utility of CMSE as a sustainable nutraceutical or functional agent for managing obesity and related disorders.