Oxycodone is a semi-synthetic opioid drug that is used to alleviate acute and chronic pain. However, oxycodone is often abused and, when taken at high doses, can induce powerful CNS depression that manifests in respiratory abnormalities, hypotension, coma, and death. Here, we employed several techniques to examine the effects of intravenous oxycodone at a wide range of doses on various metabolism-related parameters in awake, freely-moving rats. High-speed amperometry was used to assess how oxycodone affects oxygen and glucose levels in the nucleus accumbens (NAc). These measurements were supplemented by recordings of locomotor activity and temperature in the NAc, temporal muscle, and skin. At low doses, which are known to maintain self-administration behavior (0.15–0.3 mg/kg), oxycodone transiently decreased locomotor activity, induced modest brain and body hyperthermia, and monotonically increased NAc oxygen and glucose levels. While locomotor inhibition became stronger with higher oxycodone doses (0.6–1.2 mg/kg), NAc oxygen and glucose transiently decreased and subsequently increased. High-dose oxycodone induced similar biphasic down-up changes in brain and body temperature, with the initial decreases followed by increases. While cerebral vasodilation induced by neural activation appears to be the underlying mechanism for the correlative increases in brain oxygen and glucose levels, respiratory depression and the subsequent drop in blood oxygen likely mediate the brain hypoxia induced by large-dose oxycodone injections. The initial inhibitory effects induced by large-dose oxycodone injections could be attributed to rapid and profound CNS depression—the most dangerous health complication linked to opioid overdose in humans.