Liver injury/dysfunction developing in patients with sepsis may lead to an increased risk of death. Small-volume resuscitation with hyperoncotic albumin (HA) has been proposed to restore physiologic hemodynamics in hemorrhagic and septic shock. We evaluated whether HA resuscitation could alleviate the development of liver injury/dysfunction in rats with polymicrobial sepsis induced by cecal ligation and puncture (CLP). The male Wistar rats received 0.9% saline or HA (25%, 3 mL/kg intravenously) at 3 h after CLP or sham operation. All hemodynamic and biochemical variables were measured during the 18-h observation. After 18 h of CLP, the septic rats developed circulatory failure (i.e., hypotension, tachycardia, and poor tissue perfusion), liver injury (examined by biochemical variables and histologic studies), and a higher mortality. Hyperoncotic albumin not only ameliorated the deterioration of hemodynamic changes but also attenuated neutrophil infiltration and cell death in the liver of septic animals. The septic rats treated with HA had a higher survival when compared with those with 0.9% saline treatment. Moreover, the increased plasma IL-1β, plasma IL-6, plasma nitrite/nitrate concentrations, liver iNOS expression, and liver superoxide levels in CLP rats were attenuated after administration of HA. Thus, HA may be regarded as a potential therapeutic agent in the early treatment of septic shock to prevent or reduce subsequent liver failure.