Infertility is a worldwide reproductive health problem and there are still many unknown etiologies of infertility. In recent years, increasing evidence emerged and confirmed that epigenetic regulation played a leading role in reproduction. However, the function of m6A modification in infertility remains unknown. Here we report that METTL3-dependent m6A methylation plays an essential role in female fertility via balancing the estrogen and progesterone signaling. Analysis of GEO datasets reveal a significant downregulation ofMETTL3expression in the uterus of infertile women with endometriosis or recurrent implantation failure. Conditional deletion ofMettl3in female reproductive tract by using aPgr-Cre driver results in infertility due to compromised uterine endometrium receptivity and decidualization. m6A-seq analysis of the uterus identifies the 3’UTR of several estrogen-responsive genes with METTL3-dependent m6A modification, likeElf3andCelsr2, whose mRNAs become more stable uponMettl3depletion. However, the decreased expression levels of PR and its target genes, includingMyc, in the endometrium ofMettl3cKO mice indicate a deficiency in progesterone responsiveness. In vitro,Mycoverexpression could partially compensate for uterine decidualization failure caused byMettl3deficiency. Collectively, this study reveals the role of METTL3-dependent m6A modification in female fertility and provides insight into the pathology of infertility and pregnancy management.