The widely used Di-(2-ethylhexyl) phthalate (DEHP) has been reported to exhibit ubiquitous environmental and global health hazards. The bioaccumulation and environmental persistence of DEHP can cause serious health hazards in wildlife animals and human. However, DEHP-induced nephrotoxicity in bird is remained unknown. Thus, this study explored the related mechanism of DEHP nephrotoxicity in quail. For this purpose, quail were exposed with DEHP at doses of 0, 250, 500, and 1000 mg/kg body weight daily by gavage administration for 45 days. The results showed that DEHP exposure induced renal injury, oxidative stress, and endoplasmic reticulum (ER) degeneration. Low level DEHP (250 mg/kg) exposure inhibited Nrf2 signaling pathway and induced renal injury via oxidative stress and suppressed the unfolded protein response (UPR) signaling pathway and induced ER stress in the kidney. But surprisingly, high level DEHP (500 mg/kg and 1000 mg/kg) exposure activated Nrf2 and UPR signaling pathways and protected kidney, but they still couldn't resist the toxicity of DEHP. Our study demonstrated that DEHP-induced nephrotoxicity in quail was associated with activating Nrf2-mediated antioxidant defense response and UPR signaling pathway. DEHP exposure induced renal injury and destroyed the pathophysiological integrity of the kidney in quail. DEHP-induced nephrotoxicity is associated with oxidative stress, which could be regulated by Nrf2-mediated defense response. DEHP exposure activated the UPR signaling pathway to prevent ER stress in the kidney. Display omitted •DEHP-induced nephrotoxicity is associated with oxidative stress.•DEHP activates Nrf2 signaling pathway in the kidney.•DEHP-induced nephrotoxicity triggers renal ER stress.•DEHP activates UPR in the kidney.•DEHP induces crosstalk between UPR and Nrf2-mediated antioxidant defense in renal injury. DEHP-induced nephrotoxicity is associated with crosstalk between activated UPR and Nrf2-mediated antioxidant defense mechanism.