5-fluorouracil (FU) is the most common drug used as chemotherapeutic, but its hepatotoxic side effect threats its clinical application use. In consequence, searching for hepatoprotective agents is urgent necessity to hepatic hazards prevention. The present study investigated the protective effect of Chlorella vulgaris (CV) and Sugarcane (Saccharum officinarum L., SO) against FU-induced hepatotoxic effects. Sixty male Wister albino rats were used in our study that divided into 6 groups. The rats treated for 2 weeks as following: The control group rats were orally received distilled water daily, FU group rats received FU (150 mg/kg, IP, on 8^th day), and CV group received CV (400 mg/kg, orally, daily). SO group received SO (15mL/kg, orally, daily), FU+CV, and FU+SO groups. Moreover, FU caused an elevation in serum ALT, AST activities, hepatic malondialdehyde (MDA) and nitric oxide (NO) contents with decrease of catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH) content significantly. FU also caused severe histopathological alterations including degenerative, vascular, and inflammatory in the liver, along with activation of caspase-3, and COX-2 expression. Contrariwise, the concomitant treatment by CV and SO with FU ameliorated the previous biochemical, pathological, and histochemical adverse effects induced by FU. In conclusion, CV and SO have protective role against FU-induced hepatic damage, perhaps through their antioxidant, anti-apoptotic, and anti-inflammatory properties.