Synedrella nodiflora is a medicinal plant that is used by the natives of Sabah, Malaysia to treat rheumatism and several other ailments. This study aims to evaluate the ability of the crude aqueous extract of S. nodiflora leaves to protect against carbon tetrachloride (CCl4)-mediated hepatic injury in rats. S. nodiflora aqueous extract was orally administered to adult Sprague Dawley rats once daily for 14 days (150 and 300 mg/kg body weight [b.w.]) before CCl4 oral treatment (1.0 mL/kg b.w.) on the 13th and 14th days. Serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), hepatic antioxidant enzymes, and malondialdehyde (MDA) levels were estimated. Immunohistochemistry was performed for oxidative stress markers (4-hydroxynonenal [HNE], 8-hydroxy-deoxyguanosine [8-OHdG]) and proinflammatory markers (tumor necrosis factor-α, interleukin-6, prostaglandin E2). Biochemical, immunohistochemical, histological, and ultrastructural findings were in agreement to support the hepatoprotective effect of S. nodiflora against CCl4-mediated oxidative hepatic damage. Hepatoprotective effects of S. nodiflora might be attributable to the presence of phenolic antioxidants and their free radical scavenging property.