Despite extensive investigation on the toxicity of microplastics (MPs), an emerging global concern, little is known about the combined toxicity of MPs and co-occurring pollutants in aquatic environments. In this study, the combined toxicity of polystyrene MPs and sulfamethoxazole (SMZ) antibiotics was explored in zebrafish embryos in terms of the developmental, physiological, and endocrine toxicities. Exposure to PS and SMZ induced mortality (rate: 25.0 ± 7.5%) and malformation (rate: 20~35%) at multiple regions and stages of zebrafish development. Physiological toxicity was also induced as shown by the significant decrease in fetal movement (by 31.1~37.0%) and swimming frequency (by 26.9~36.8%) and the increase in heartbeat rate (by 19.0~20.9%). Finally, PS and SMZ exposure also induced extensive endocrine toxicities in zebrafish as confirmed by increases in various biomarkers including vitellogenin, 17β-estradiol, testosterone, and triiodothyronine. The combination index showed that antagonistic effects were present between PS and SMZ toxicity, which slightly decreased their combined toxicity. This study aims to further understand the combined toxicity of MPs and co-occurring pollutants in aquatic environments.