BACKGROUND: The swine Sertoli cells (SCs) are more vulnerable to the environmental insults than other species. We observed that zearalenone (ZEA), a prevalent food contaminant, caused SCs oxidative damage and inhibits their proliferation. Therefore, a naturally occurring antioxidant, i.e., the deer blood phospholipids (DBP) has been selected to test its potentially protective effects on SCs. METHODS: Collect fresh samples of swine testicles, isolated, cultured and identified primary swine SCs. The ROS levels in SCs 24 h induced by different concentrations of ZEA were detected, and the oxidative damage model was established. After DBP was added to the SCs 24 h after the damage, the oxidative and antioxidant indexes were detected by ELISA kit. Finally, the protective mechanism of DBP was explained by RNA-seq. RESULTS: The results showed that DBP effectively protected against the reproductive toxicity induced by ZEA. The protective effects of DBP were mainly mediated by its potent antioxidative capacity. DBP upregulated the activities of the endogenous antioxidant enzymes including CAT and GSH-PX and reduced intracellular ROS level and MDA. In addition, DBP also promoted the SCs proliferation. The transcriptome sequencing combined with DEGs, GO and KEGG analyses suggested that DBP treatment enriched various signaling pathways of potentially biological significance including MAPK and PI3K-Akt signaling pathways. Both pathways also promote the cell proliferation. EdU assay further confirmed the beneficial effects of DBP on SCs proliferation.