Co-existence of mycotoxins may pose a greater risk. It remains less known about the toxic effect of co-exposure of zearalenone (ZEA) and deoxynivalenol (DON) on aquatic life. In the present study, the toxic effects of the combine treatment of ZEA and DON on zebrafish (Danio rerio) embryos were investigated. The results showed that the combined treatment of ZEA (200, 400, 800 μg/L) and DON (4000 μg/L) did not cause apparent deaths, but induced a developmental toxicity as indicated by decreased movement times and heartbeat. At 96 h post-fertilization (hpf), co-exposure of ZEA and DON (Z400 + D4000 and Z800 + D4000 group) led to significant oxidative stress as evidenced by the increased ROS level and MDA content, as well as the changes of antioxidant enzymes (SOD, CAT and GPX) and their genes. Besides, the combined treatment of ZEA and DON triggered hepatotoxicity as shown by the changes of Fabp10a, Gclc, Gsr, Nqo1 genes, apoptosis through upregulating apoptosis-related genes (p53, Caspase-9, Caspase-3) and downregulating Bcl-2 gene, as well as inflammation by promoting the expression of IL-1β, IL-6, TNF-α, TLR4, MyD88, NF-κBp65 genes. These results indicated the co-exposure of ZEA and DON caused oxidative stress, leading to stronger potential toxic effects to zebrafish embryos than their respective single treatment. Therefore, more attention should be paid to risk management of the co-contamination of mycotoxins.