Acute kidney injury (AKI) is a frequent complication after liver transplantation (LT). The mechanism of post-LT AKI remains unclear. We used the rat model of syngeneic orthotopic LT (SOLT) to investigate the mechanism of post-LT AKI. We hypothesized that the condition of the graft, rather than intraoperative hemodynamic instability, has an important role in post-LT AKI in the SOLT model. Rats were randomly assigned into four groups: sham-operated group; vessel-clamped group; full-size LT group; and reduced-size LT group. We identified AKI in both full-size and reduced-size LT groups. In addition to renal tubular necrosis and apoptosis, renal peritubular capillary injury was also present. Pathological changes were more severe in the reduced-size than in the full-size LT group. We found that the systemic inflammatory response induced by LT was the initiating factor in post-LT AKI. This is the first study to investigate the pathological mechanism of AKI in an animal model of SOLT. Our results demonstrate that protection of the liver graft and inhibition of the systemic inflammatory response are vital in reducing the risk of post-LT AKI.