Exposure to phoxim at low levels caused bioaccumulation with neurotoxicity but also induced oxidative stress, tissue damage, and abnormal nutrient metabolism. This study described that vitamin E ameliorates phoxim-induced nephrotoxicity via inhibiting mitochondrial apoptosis. In vivo, 24 healthy piglets were treated with phoxim (0 mg/kg and 500 mg/kg) and vitamin E + phoxim (vitamin E + phoxim: 200 mg/kg + 500 mg/kg). In vitro, PK15 cells were treated with phoxim (0 mg/L and 1 mg/L) and vitamin E + phoxim (phoxim + vitamin E: 1 mg/L + 1 mg/L) for 12 h and 24 h. Our results indicated that accumulation of ROS, oxidative stress, and renal cell injury through stimulation of mitochondrial apoptosis resulted in phoxim-induced nephrotoxicity. Phoxim resulted in swollen mitochondria, blurred internal cristae, renal glomerular atrophy, and renal interstitial fibrosis. Vitamin E alleviated the adverse effects of phoxim by reducing ROS and improving antioxidant capacity in vivo and in vitro. Vitamin E significantly increased SDH in vitro (p < 0.01), while it decreased ROS, Bad, and cyto-c in vitro and SOD and CAT in vivo (p < 0.05). Vitamin E ameliorated phoxim-induced renal histopathologic changes, and mitochondria swelled. In addition, vitamin E regulates phoxim-induced apoptosis by alleviating oxidative damage to the mitochondria.