Cachexia, a condition characterized by significant loss of body weight and muscle mass, affects 50–80% of cancer patients and contributes to 20% of cancer-related deaths. The underlying mechanisms of cachexia remain poorly understood. This study identifies lactate as a key factor in driving cancer cachexia. Circulating lactate levels are positively correlated with body weight loss in cancer patients and mouse models of cancer cachexia. Lactate infusion alone is sufficient to induce a cachectic phenotype in tumor-free mice. Adipose-specific deletion of G-protein-coupled receptor (GPR)81, similar to global GPR81 deficiency, ameliorates lactate-induced or tumor-induced wasting in male mice. Mechanistically, lactate/GPR81-induced cachexia occurs independently of the protein kinase A (PKA) pathway but is mediated by a signaling cascade involving Gi–Gβγ–RhoA/ROCK1–p38. These findings suggest that targeting GPR81 could be a promising therapeutic approach for treating this life-threatening complication of cancer.Cachexia, a condition characterized by significant loss of body weight and muscle mass, affects 50–80% of cancer patients and contributes to 20% of cancer-related deaths. The underlying mechanisms of cachexia remain poorly understood. This study identifies lactate as a key factor in driving cancer cachexia. Circulating lactate levels are positively correlated with body weight loss in cancer patients and mouse models of cancer cachexia. Lactate infusion alone is sufficient to induce a cachectic phenotype in tumor-free mice. Adipose-specific deletion of G-protein-coupled receptor (GPR)81, similar to global GPR81 deficiency, ameliorates lactate-induced or tumor-induced wasting in male mice. Mechanistically, lactate/GPR81-induced cachexia occurs independently of the protein kinase A (PKA) pathway but is mediated by a signaling cascade involving Gi–Gβγ–RhoA/ROCK1–p38. These findings suggest that targeting GPR81 could be a promising therapeutic approach for treating this life-threatening complication of cancer.