Background and aims Cyclophosphamide (CPh) is a frequently used drug, in human and animals for its immunosuppressive and anticancer potential. However, it is metabolized by the liver yielding damaging toxicants (to the liver itself and other non-target vital organs) via oxidative stress, apoptosis induction and finally necrosis. Since there is no escaping of using such harmful medications, we focused on alleviating its side-effects. Panax ginseng Meyer is a potent candidate, and we still lack adequate information on its hepatoprotective role against cyclophosphamide-induced liver-damage. Methods Here, we used P. ginseng (Korean Red Ginseng) compared to vitamin-E (natural antioxidant) in combating CPh-induced liver damage. Forty-eight albino rats were divided into 6 groups, Control, Ginseng, Vitamin E, Cyclophosphamide (CPh), CPh + Ginseng or CPh + Vitamin-E. Blood samples were taken for biochemical analyses and liver samples were collected for histopathology, oxidative stress evaluation, and gene expression analyses. Results In CPh group, typical CPh-liver damage was evident (higher levels of AST, ALT, ALP; lower albumin and total proteins levels; lower liver tissue concentrations of SOD, GPX and CAT and higher MDA; injured liver histopathological picture; and finally increased TNF-α, IL-1β and Caspase3 and decreased BCL-2 genes expression). All these were abolished with either P. ginseng or vitamin-E administration. However, P. ginseng was overall superior to vitamin-E, especially in restoring blood biochemical findings and damaged histopathological picture. Conclusions Therefore, P. ginseng is a potent hepatoprotector (vitamin-E to a lesser extent) and should be considered where liver damage is expected secondary to damaging medications; as cyclophosphamide.