The current work was designed to study the potential of N-acetylcysteine (NAC) in modulating hyperoxaluric manifestations induced by acute oxalate dose in rat liver. Hyperoxaluric conditions were induced by giving a single dose of sodium oxalate (70 mg/kg body weight) in one group, and in the other group, hyperoxaluric rats were administered NAC (200 mg/kg body weight) after 30 min of the oxalate dose. After 12 h of the above treatment, blood was taken from the orbital sinus for testing serum oxalate, and animals were sacrificed. To exploit the potential of NAC, various oxidative stress parameters [lipid peroxidation (LP) and activity of antioxidant enzymes], lipid content, and histologic analysis of rat liver were performed. The increased level of LP and activities of superoxide dismutase and catalase in hyperoxaluric rats were restored after NAC treatment. Not only the decreased amount of total lipids and phospholipids but also the increased ratio of cholesterol/phospholipid (showing decreased membrane fluidity) in hyperoxaluric rats were balanced by NAC treatment. Further restored histologic changes of liver tissue confirmed the protective antioxidant effects of the given drug. Thus, N-acetylcysteine being an extraneous antioxidant showed curative properties toward hyperoxaluric manifestations in liver.