Recently, research on the biological effects of microplastics (MPs) has grown exponentially. However, effects of MPs on freshwater fishes and the mechanisms of the biological effects of MPs were limited. So, the purpose of the current study was to clarify the effects of microplastics on oxidative stress response, DNA fragmentation, and proteinogram of the early juvenile stage of Nile Tilapia (Oreochromis niloticus). The fishes were assigned into four groups: one control, three MPs-exposed groups as 1 mg/L of MPs, 10 mg/L of MPs, and 100 mg/L of MPs respectively for 15 days and 15 days of recovery. The activities of superoxide dismutase, catalase, total peroxides, and oxidative stress index (OSI), as well as lipid peroxidation and DNA fragmentation, increased in groups exposed to MPs compared to the control group in a dose-dependent manner. In contrast, the activity of total antioxidant capacity decreased in groups exposed to MPs compared to the control group in a dose-dependent manner. The electrophoretic pattern of muscle proteins revealed alteration in the proteinogram in the MPs-exposed groups compared to control. After the recovery period, the activities of superoxide dismutase, catalase, total peroxides, total antioxidant capacity, lipid peroxidation, DNA fragmentation, and the electrophoretic pattern of muscle proteins returned to normal levels in 1 mg/L of MPs-exposed group. Combined with our previous work, these results suggest that MPs cause the overproduction of reactive oxygen species (ROS) and alters the antioxidants parameters, resulting in oxidative stress and DNA damage. The present study fosters a better understanding of the toxic effects of MPs on Tilapia as a freshwater model.