Argonaute proteins and their interacting small RNAs play a key role in regulating complementary mRNA targets during animal development. Here, we investigate a novel and essential function of the catalytically active Argonaute protein CSR-1 in maternal mRNA degradation during early embryogenesis in Caenorhabditis elegans. We show that CSR-1 interacts with endogenous small RNAs antisense to hundreds of cleared maternal mRNAs in embryos, and preferentially cleaves mRNAs no longer engaged in translation. The depletion of CSR-1 during maternal to zygotic transition leads to embryonic lethality in a catalytic-dependent manner and impairs the degradations of its embryonic mRNA targets. Given the conservation of Argonaute catalytic activity, we propose that a similar mechanism operate to clear maternal mRNAs during maternal to zygotic transition across species.