Chronic neuropathic pain resulting from peripheral nerve damage is a significant clinical problem, which makes it imperative to develop the mechanism-based therapeutic approaches. Enhancement of endogenous cannabinoids by blocking their hydrolysis has been shown to reduce inflammation and neuronal damage in a number of neurological disorders and neurodegenerative diseases. However, recent studies suggest that inhibition of their hydrolysis can shift endocannabinoids 2-arachidonoyl glycerol (2-AG) and anandamide (AEA) toward the oxygenation pathway mediated by cyclooxygenase-2 (COX-2) to produce proinflammatory prostaglandin glycerol esters (PG-Gs) and prostaglandin ethanolamides (PG-EAs). Thus, blocking both endocannabinoid hydrolysis and oxygenation is likely to be more clinically beneficial. In this study, we used the chronic constriction injury (CCI) mouse model to explore the therapeutic effects of simultaneous inhibition of AEA hydrolysis and oxygenation in the treatment of neuropathic pain. We found that the fatty acid amide hydrolase (FAAH) inhibitor PF04457845 and the substrate-selective COX-2 inhibitor LM4131 dose-dependently reduced thermal hyperalgesia and mechanical allodynia in the CCI mice. In addition to ameliorating the pain behaviors, combined treatment with subeffective doses of these inhibitors greatly attenuated the accumulation of inflammatory cells in both sciatic nerve and spinal cord. Consistently, the increased proinflammatory cytokines IL-1β, IL-6, and chemokine MCP-1 in the CCI mouse spinal cord and sciatic nerve were also significantly reduced by combination of low doses of PF04457845 and LM4131 treatment. Therefore, our study suggests that simultaneous blockage of endocannabinoid hydrolysis and oxygenation by using the substrate-selective COX-2 inhibitor, which avoids the cardiovascular and gastrointestinal side effects associated with the use of general COX-2 inhibitors, might be a suitable strategy for the treatment of inflammatory and neuropathic pain.