The transition from fertilized oocyte to totipotent embryo relies on maternal factors that are synthetized and accumulated during oocyte development. Yet, it is unclear how oocytes regulate the expression of maternal genes within the transcriptional program of oogenesis. Here, we report that the Drosophila Trithorax group protein dMLL3/4 (also known as Trr) is essential for the transition to embryo fate at fertilization. In the absence of dMLL3/4, oocytes develop normally but fail to initiate the embryo mitotic divisions after fertilization. This incapability results from defects in paternal genome reprogramming and maternal meiotic completion. The methyltransferase activity of dMLL3/4 is dispensable for both these processes. We further show that dMLL3/4 promotes the expression of a functionally coherent gene subset that is required for the initiation of post-fertilization development. Accordingly, we identify the evolutionarily conserved IDGF4 glycoprotein (known as oviductin in mammals) as a new oocyte-to-embryo transition gene under direct dMLL3/4 transcriptional control. Based on these observations, we propose that dMLL3/4 plays an instructive role in the oocyte-to-embryo transition that is functionally uncoupled from the requirements of oogenesis.