Ganoderma lucidum (G.L) is a well-known mushroom that is used extensively nowadays to treat or prevent a variety of diseases, such as heart disease, liver dysfunction, cancer and kidney failure due to its excellent antioxidant activities. Therefore, the objective of present investigation was to evaluate whether G.L could mitigate oxidative stress and avert hepatorenal injury induced by trihalomethanes (THMs) in adult male Wistar albino rats. Forty male Wister rats (130 ± 15 g) were allocated into 4 equal groups (10 rats/group) as follows: Group (1) rats kept as control, whereas group (2) rats received G.L (600mg / kg B.W daily) orally by stomach tube; group (3) rats were intoxicated with THMs (16.17mg / kg B.W daily, injected i.p); group (4) rats were treated with THMs along with G.L for 30 days. After one month of the trial, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein (T.P) and albumin (Alb), triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), creatinine (Cr), urea (Ur), uric acid (UA) and blood urea nitrogen (BUN) were estimated in blood sera. Meanwhile, oxidative stress markers including catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione reduced content (GSH) and malondialdehyde (MDA) were performed in liver and kidney tissue homogenates. The results of this study declared that THMs declined the levels of Alb, T.P, HDL-C, renal and hepatic antioxidants (SOD, GPx, CAT and GSH) while raising the levels of ALT and AST, TC, TGs and LDL-C, kidney function markers, as well as MDA. Administration of G.L to THMs-intoxicated rats reversed the effect of THMs, prevented oxidative stress and provided strong antioxidant protection against THMs induced hepato-renal toxicity.