Abstract: Organophosphorus (OP) insecticides constitute one of the most widely used classes of pesticides being employed for both agricultural and landscape pest control. The purpose of this study was to investigate the effect of dimethoate (DM), an organophosphorus insecticide, on some biochemical and histopathological parameters in liver of adult male guinea pigs as well as the possible role of Withania somnifera extract in attenuation of DM-induced hepatotoxicity. The animals were divided randomly into 5 groups and kept at 5 animals per group in an environmentally controlled condition with free access to food and water ad libitum. The first group was served as a control group and administered with olive oil orally; the group II received aqueous extract of W. somnifera (100 mg kg-1 b.wt.) orally, group III, IV and V was administered with DM (14 mg kg-1; 1/25LD50) for 21 days orally. Group IV and V received 100 mg kg-1 of W. somnifera extract and silymarin, respectively half hour before DM administration for 21 days. DM caused a statistically significant increase in the serum level of liver enzymes (AST, ALT, ALP) when compared to control animals, whereas, W. somnifera and silymarin pre-treatment to the DM-intoxicated animals resulted in a significant normalization of the enzymes activities. On the other hand W. somnifera extract reduced the incidence of histopathological changes such as cytoplasmic vacuolization and degeneration in nuclei, rupture of epithelia lining the central vein, widened sinusoidal space and lymphocyte infiltration induced by DM treatment in guinea pigs. In conclusion, the results of this study suggest that W. somnifera aqueous extract could protect the liver against DM-induced oxidative damage.