Background: Acute kidney injury (AKI) impacts the survival of liver transplant recipients severely. To date, the related mechanism and effective therapy have not been rigorously explored. The present study aimed to explore the role of p53-mediated autophagy in the protective effect of hydrogen-rich saline (HRS) on AKI after orthotropic liver transplantation (OLT). Methods: Adult male Sprague-Dawley rats were randomly allocated into four groups: sham, OLT, OLT with HRS (6 ml/kg) pretreatment (HS), OLT with HRS and chloroquine pretreatment (60 mg/kg) group (CQ). All the samples were collected 6 hours after reperfusion. The renal function and oxidative stress level were measured by biochemical and histopathologic examinations. The formation of autophagosome was observed by transmission electron microscopy. The apoptotic rate was determined by terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling analysis. The expression of caspase-3, cytochrome c, p53, damage-regulated autophagy modulator, Becline-1, microtubule-associated protein light 3-II, p62, lysosome-associated membrane protein-2, and the phosphorylation of p53 were assayed by western blot assay. Results: Compared with the OLT group, HRS dramatically attenuated the histopathologic damage, restored the renal function, and decreased the oxidative stress level. Simultaneously, HRS significantly ameliorated apoptosis by decreasing the apoptotic rate and inhibiting the expression of caspase-3 and cytochrome c in rats subjected to OLT. The expression of Becline-1 and microtubule-associated protein light 3-II were upregulated with the inhibition of p62 and lysosome-associated membrane protein-2. The inhibition of autophagy by chloroquine counteracted the renoprotective effects of HRS. Conclusions: HRS is able to protect against AKI after liver transplantation partly by reducing apoptosis, which is possibly involved in the modulation of p53-mediated autophagy.