Nucleotide-binding domain and leucine-rich repeat (NLR) proteins are well-known for their key roles in the immune system. Ectopically expressed NLRP2 in immortalized cell lines assembles an inflammasome and inhibits activation of the proinflammatory transcription factor NF-κB, but the physiological roles of NLRP2 are unknown. Here, we show that Nlrp2-deficient mice were born with expected Mendelian ratios and that Nlrp2 was dispensable for innate and adaptive immunity. The observation that Nlrp2 was exclusively expressed in oocytes led us to explore the role of Nlrp2 in parthenogenetic activation of oocytes. Remarkably, unlike oocytes of young adult Nlrp2-deficient mice, activated oocytes of mature adult mice developed slower and largely failed to reach the blastocyst stage. In agreement, we noted strikingly declining reproductive rates in vivo with progressing age of female Nlrp2-deficient mice. This work identifies Nlrp2 as a critical regulator of oocyte quality and suggests that NLRP2 variants with reduced activity may contribute to maternal age-associated fertility loss in humans.