Ovulation is triggered by the gonadotropin surge that induces the expression of two key genes, progesterone receptor (Pgr) and prostaglandin-endoperoxide synthase 2 (Ptgs2), in the granulosa cells of preovulatory follicles. Their gene products PGR and PTGS2 activate two separate pathways that are both essential for successful ovulation. Here, we show that the PGR plays an additional essential role: it attenuates ovulatory inflammation by diminishing the gonadotropin surge-induced Ptgs2 expression. PGR indirectly terminates Ptgs2 expression and PGE2 synthesis in granulosa cells by inhibiting the nuclear factor κB (NF-κB), a transcription factor required for Ptgs2 expression. When the expression of PGR is ablated in granulosa cells, the ovary undergoes a hyperinflammatory condition manifested by excessive PGE2 synthesis, immune cell infiltration, oxidative damage, and neoplastic transformation of ovarian cells. The PGR-driven termination of PTGS2 expression may protect the ovary from ovulatory inflammation. Display omitted •Successful ovulation requires timely expression of PGR in the ovarian granulosa cells•PGR terminates LH-surge-driven PGE2 synthesis by decreasing PTGS2 (COX-2) expression•Impaired PGR expression leads to hyperinflammation and tissue damage in the ovary A preovulatory LH surge induces the expression of PGR and the production of PGE2, a proinflammatory prostaglandin, in preovulatory granulosa cells. Park et al. show that PGR then suppresses PGE2 synthesis by decreasing the expression of PTGS2. Such PGR-driven termination temporarily confines ovulatory inflammation within a short period.