Objectives: Perfluorooctane sulfonate (PFOS) and zinc oxide nanoparticles (ZnO-NPs) are frequently detected in the environment but few studies have assessed the joint toxicity of them. Oxidative stress and apoptosis to zebrafish (Danio rerio) embryos induced by the PFOS and ZnO-NPs were investigated in this study. Material and Methods: The embryos were exposed to the PFOS (0, 0.4, 0.8 and 1.6 mg/l), ZnO-NPs (12.5, 25, 50 mg/l) and PFOS plus ZnO-NPs (0.4+12.5, 0.8+25 and 1.6+50 mg/l) mixture solutions until 96 h post-fertilization. Activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (Gpx) and malondialdehyde (MDA) content were measured in zebrafish embryos after exposure lasting for 96 h. At the same time, the genes expression related to reactive oxygen species (ROS) generation, oxidative damage and apoptosis were also measured. Results: A significant induction of the ROS accompanied by the increase in the activity of the Gpx and MDA contents were found in co-treatment groups. Furthermore, several apoptosis pathway related genes such as Bax, p53, caspase-3 and caspase-9 were significantly up-regulated in the PFOS plus ZnO-NPs exposure groups, while anti-apoptotic gene Bcl-2 was significantly down-regulated in the PFOS plus ZnO-NPs exposure groups. In addition, some oxidative stress-related genes such as Cat, GSH peroxidase 1 (Gpx1a) and superoxide dismutase 1 (Sod1) were also significantly down-regulated after the PFOS plus ZnO-NPs co-treatments. Conclusions: The results demonstrated that the PFOS plus ZnO-NPs co-exposure could cause more serious oxidative stress and apoptosis than the PFOS and ZnO-NPs exposure alone at the exposure concentrations above. The synergistic effects of the PFOS and ZnO-NPs may be the important mechanisms of their toxicity to zebrafish embryos. Int J Occup Med Environ Health 2017;30(2):213–229