Hepatic ischemia and reperfusion (IR) injury is a common complication in clinical practice. Endoplasmic reticulum (ER) stress and autophagy are the key factors in the process of hepatic IR injury. The vitamin D receptor (VDR) can mediate ER stress and autophagy; however, it can also mitigate IR injury. The relationship between VDR, ER stress, and autophagy in hepatic IR injury is unknown. VDR knockout mice and wild-type littermates underwent 70% liver ischemia (90 min) and reperfusion (6 h). To observe the effect of autophagy in the relationship with VDR and ER stress in hepatic IR injury, the autophagy agonist rapamycin and its inhibitor chloroquine were used in the study. Meanwhile, RAW264.7 cells were studied in vitro to verify the relationship between VDR, autophagy, and ER stress. VDR was involved in hepatic IR injury and its activation reduced liver injury and inhibited an inflammatory response. ER stress took part in the liver injury during the process of IR. Meanwhile, VDR activation was found to inhibit inflammation by ER stress, and vice versa. Furthermore, autophagy was the connection between VDR and ER stress. After treatment with rapamycin or chloroquine, the effect of VDR activation or VDR silencing in ER stress was partially reversed. The same tendency was observed in vitro. ER stress and autophagy are important mechanisms of hepatic IR injury. VDR can regulate ER stress through autophagy and then protect the liver from IR injury.