Background: Liver ischemia/reperfusion (I/R) commonly happens within liver surgical procedures as well as transplantation. It causes postoperative liver dysfunction, and poor patient outcome. Emerging strategies assume that efficacy of mesenchymal stem cells-exosomes (MSCs-EXOs) is dependent on status of MSCs extracellular environment. Hydrogen sulfide (H₂S) regulates several cellular signaling pathways and exerts a protective effect in various disorders. Aim of the work: Comparing the protective influence of co-administration of H₂S and exosomes versus H₂S-preconditioned exosomes on liver I/R injury adult male rat model. Materials and Methods: Fifty adult male rats were categorized to donor, control, liver I/R, recovery, H₂S + EXOs, and H₂S-preconditioned EXOs groups. At the end of experiment, biochemical analysis [for liver enzymes, nuclear factor kappa-B (NF-κB) and superoxide dismutase (SOD)], histological and immunohistochemical studies [for high-mobility group box 1 (HMGB1), nuclear factor-erythroid 2-related factor 2 (Nrf2), as well as heme oxygenase-1 (HO-1)], and statistical analysis were done. Results: Ischemia/reperfusion group recorded significant rise in hepatic enzymes, NF-κB level, HMGB1 immunoreactivity, and decrease in SOD level, Nrf2 and HO-1 immunoreactivity. In addition to the presence of foci of disorganized hepatocytes, necrotic cells, apoptosis, and periportal inflammatory infiltration. Recovery showed insignificant improvement in formerly mentioned results. While the use of H₂S + EXOs, or H₂S-precoordinated EXOs clearly improved inflammation, antioxidant parameters, and hepatocellular injury. Conclusion: H₂S + EXOs in addition to H₂S-precoordinated EXOs possessed hepatoprotective impacts against I/R injury in the liver. Whereas H₂S preconditioning of MSCs could augment the protective impact of MSC-EXOs.