Emerging evidence suggests that the δ-opioid receptor (DOR) is neuroprotective against hypoxic stress. Since inflammatory factors play an important role in hypoxic injury, we sought to determine if DOR modulates cellular inflammatory process in hypoxia. Since astrocytes produce inflammatory cytokines and play a major role in inflammatory response to hypoxia, we exposed cultured rat astrocytes to severe hypoxia (0.1% O2) for 3-6 h to examine if DOR activation altered hypoxia-induced expression of proinflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) along with cell viability. To examine a differential DOR-mediated modulation between glial and neuron-like cells, we also conducted the same experiments in differentiated PC-12 cells. We found that hypoxia reduced cell viability in both astrocytes and PC-12 cells, and DOR activation with UFP-512 (5 μM) effectively protected both the cells against hypoxic insult. Hypoxia markedly increased TNF-α levels in the astrocytes (p < 0.05); however, the same hypoxic stress reduced TNF-α levels in the PC-12 cells. Exogenous addition of TNF-α to the culture media further worsened the hypoxia-induced damage in PC-12 cells. Hypoxia increased the DOR-expression in astrocytes but not in PC-12 cells. DOR-activation reversed the hypoxia-induced changes in TNF-α levels in both the cells. In contrast, the IL-1β levels did not significantly alter in astrocytes and PC-12 cells when exposed to the same hypoxic conditions or following DOR activation. Our novel data suggest that DOR activation inhibits TNF-α mediated inflammatory processes following exposure to severe hypoxia with a differential regulation between glial vs. neuron-like cells.