Opioid analgesics are widely used to manage moderate to severe pain in cancer patients. The μ opioid receptor (MOR) is expressed in not only the brain and spinal cord, but also a wide range of peripheral sites, including the gastrointestinal tract and immune cells. It has been considered that the central µ-opioidergic system is closely associated with analgesia and euphoric effects, whereas the peripheral µ-opioidergic system is responsible for side effects such as constipation and nausea. However, little is known about the role of the endogenous µ-opioidergic system in the control of the innate immune response. In this study, we investigated the functional role of central and peripheral µ-opioidergic systems in tumor progression using a pharmacological and genetics approach. First, we found that treatment with peripheral MOR antagonists significantly decreased Lewis lung carcinoma (LLC)-graft compared to that in control mice. On the other hand, activation of the hypothalamic µ-opioidergic system using the Gq-DREADD technique significantly decreased the tumor volume compared to that in control mice. Taken together, these findings suggest that the central and peripheral µ-opioidergic systems may play a bidirectional role in the control of tumor progression.