We recently demonstrated that glucocorticoids markedly upregulate the expression of cyclooxygenase-2 in cardiomyocytes and protect hearts from ischemia–reperfusion (I/R) injury by activating lipocalin-type prostaglandin D (PGD) synthase (L-PGDS)–derived PGD ₂ biosynthesis. We examined a downstream mechanism of cardioprotection elicited by PGD ₂ biosynthesis. Acute PGD ₂ treatment did not protect hearts against I/R injury. We then speculated that PGD ₂ and its metabolite 15-deoxy-Δ12,14-PGJ ₂ activate gene expression networks to mediate the glucocorticoid-mediated cardioprotection. Using an unbiased approach, we identified that glucocorticoids induce a number of well-known erythroid-derived 2–like 2 (Nrf2) target genes in the heart in an L-PGDS–dependent manner and that the cardioprotective effect of glucocorticoids against I/R injury was not seen in Nrf2-knockout hearts. We showed relatively low expression of PGD ₂ receptors (ie, DP1 and DP2) in the heart but abundant expression of PGF _2α receptor (FP), which binds PGF _2α and PGD ₂ with equal affinity. Glucocorticoids also failed to induce the expression of L-PGDS–dependent Nrf2 target genes in FP-knockout hearts. PGD ₂ acted through its metabolite 15-deoxy-Δ12,14-PGJ ₂ in the heart as evidenced by the glucocorticoid-mediated activation of peroxisome proliferator-activated receptor-γ. In turn, glucocorticoids failed to induce the expression of L-PGDS–dependent Nrf2 target genes in hearts pretreated with peroxisome proliferator-activated receptor-γ antagonist GW9662, and glucocorticoid-mediated cardioprotection against I/R injury was compromised in FP-knockout mice and GW9662-treated mice. In conclusion, PGD ₂ protects heart against I/R injury by activating Nrf2 predominantly via FP receptor. In addition, we propose activation of peroxisome proliferator-activated receptor-γ by the dehydrated metabolite of PGD ₂ (15-deoxy-Δ12,14-PGJ ₂ ) as another mechanism by which glucocorticoids induce cardioprotection.