Obesity is a worldwide public health issue, however, efficient strategies to treat obesity without systemic damage is still in serious lack. Herein, we proved that a significant decrease in body weight and abdominal circumference was observed when monosodium glutamate (MSG)-induced obese mice were orally treated with Coicis Semen formula. Consistently, computed tomography and magnetic resonance imaging results showed that both whole-body fat content and subcutaneous fat thickness were lowered, which was further confirmed by hematoxylin-eosin staining. In addition, the weight ratios of adipose tissues and liver to the body weight were reduced, due to the decreased lipid accumulation. The increased triacylglycerol, total cholesterol, and inflammatory cytokines could also be downregulated after the treatment. Furthermore, the neuronal injury marker and inflammatory cytokines in the hypothalamus were obviously reduced after the treatment, revealing that the protective effect of Coicis Semen formula on MSG-induced obesity was achieved by alleviating hypothalamic injury.