Excessive exposure to manganese (Mn) increases levels of oxidative stressors and proinflammatory mediators, such as cyclooxygenase-2 and prostaglandin E2. Mn also activates nuclear factor-κB (NF-κB), an important mediator of inflammation. The signaling molecule 15-deoxy-Δ12,14-prostaglandin J2 (15 d-PGJ2) is an anti-inflammatory prostaglandin. Here, we tested the hypothesis that 15 d-PGJ2 modulates Mn-induced activation of astrocytic intracellular signaling, including NF-κB and nuclear factor erythroid 2-related factor (Nrf2), a master regulator of antioxidant transcriptional responses. The results establish that 15 d-PGJ2 suppresses Mn-induced NF-κB activation by interacting with several signaling pathways. The PI3K/Akt pathway, which is upstream of NF-κB, plays a role in this activation, because (i) pretreatment with 15 d-PGJ2 (10 μM for 1 h) significantly (p < 0.01) inhibited Mn (500 μM)-induced PI3K/Akt activation and (ii) inhibition of the PI3K/Akt pathway with LY29004 significantly (p < 0.05) decreased NF-κB activation. 15 d-PGJ2 also significantly (p < 0.05) attenuated Mn-induced astrocytic NF-κB activation by inhibiting the Mn-induced phosphorylation of IκB kinase and subsequent IκB-α degradation. Because Mn-induced oxidative stress is also associated with Nrf2 activation, additional studies addressed the ability of 15 d-PGJ2 to modulate the Nrf2 pathway. 15 d-PGJ2 significantly (p < 0.01) increased Nrf2 expression in whole-cell lysates. Consistent with its pro-oxidant properties, Mn also increased Nrf2 expression. Nevertheless, cotreatment of whole-cell lysates with both Mn and 15 d-PGJ2 partially suppressed (p < 0.01) the 15 d-PGJ2-induced increase in astrocytic Nrf2 protein expression. Mn treatment also decreased (p < 0.001) expression of DJ-1, a Parkinson disease-associated protein and a stabilizer of Nrf2, and 15 d-PGJ2 attenuated Mn-induced astrocytic inhibition of DJ-1 expression. Collectively, these results demonstrate that 15 d-PGJ2 exerts a protective effect in astrocytes against Mn-induced inflammation and oxidative stress by modulating the activation of the NF-κB and Nrf2 signaling pathways.