Dimethylhydrazine (DMH) is highly toxic for the different body organs, including the liver. The current study aimed to investigate the potential protective role of virgin coconut oil (VCO) and lauric acid (LA) in presence/absence of a chemotherapy drug “5-fluorouracil (5-FU)" against the hepatoxicity induced by DMH in male rats (Rattus norvegicus). Ninety rats were randomly divided into nine groups (n = 10). (G1) control group; (G2) rats received 4 mL VCO/kg body weight (b.wt) , orally/day after day for six weeks starting from week 13; (G3) rats received LA (200 mg/kg b.wt), orally/day after day for six weeks as in G2; (G4) rats were injected subcutaneously (s.c.) with DMH (20 mg/kg b.wt), once/week for the first six weeks; (G5) rats received DMH as in G4 and intraperitoneally (i.p.) injected with 5-FU (75 mg/kg b.wt), once/week starting from week 13 for three successive weeks; (G6) rats received DMH and VCO as in G4 and G2, respectively; (G7) rats received DMH and LA as in G4 and G3, respectively; (G8) rats received DMH, 5-FU, and VCO as in G4, G5, and G2, respectively; (G9) rats received DMH, 5-FU, and LA as in G4, G5, and G3, respectively. The results showed that DMH injection caused oxidative stress and histopathological alterations in the liver tissue, as well as dyslipidaemia. However, treatment of male rats with VCO or LA in presence/absence of 5-FU reduced significantly the DMH-induced hepatotoxicity.