The precise mechanisms behind early embryonic arrest due to sperm-related factors and the most effective strategies are not yet fully understood. Here, we present two cases of male infertility linked to novel variants, associated with oligoasthenoteratozoospermia (OAT) and early embryonic arrest. To investigate the underlying mechanisms and promising therapeutic approaches, knock-in and knock-out mice were generated. The variant male mice demonstrated OAT and embryonic arrest, mirroring the clinical observations of our patients. Sperm from both affected individuals and mice exhibited aberrant localization of phospholipase C zeta and oocyte activation deficiency (OAD). The application of artificial oocyte activation (AOA) effectively overcame the infertility caused by the variants, facilitating successful pregnancies and live births in both human and mice. Additionally, our research revealed that OAD influences the expression of multitude of genes at the 2-pronuclear (2PN) stage, with the gene playing a pivotal role in early embryonic arrest. The injection of mRNA can mitigate this arrest. To our knowledge, this is the first study to show that sperm-related OAD affects gene expression at the 2PN stage and elucidate how AOA overcomes male factor-derived embryonic arrest, enabling successful pregnancies and live births.