Carbon tetrachloride (CCl4) is a known ecological hazardous xenobiotic that could motivate hepatotoxicity. We aimed to examine, for the first time, the therapeutic potential of nickel(II) diacetyl monoxime-2-pyridyl hydrazone complex versus CCl4-induced hepatotoxicity in rats. We used six rat groups of ten animals each. The negative control, vehicle, normal rats injected i.p. with the complex (2.4 mg/kg/day), positive control rats injected i.p. with CCl4, and treated rats administered complex via injection at low and high concentrations of 1.2 and 2.4 mg/kg/day, respectively at the same time as CCl4 injection for short-term (3-weeks) and long-term (8-weeks) treatment. Intoxicated-rodents exhibited significant elevations in the liver index, hepatic serum markers, and oxidative stress with significant reductions in the hepatic, antioxidants, nucleic acids, and proteins. Complex co-treatment with CCl4 significantly suppressed the elevated liver enzyme activities, attenuated oxidative stress, reactivated antioxidant-system components, and amended the hepatic tissue injury. The complex high dose was more efficient than the low dose. Results of negative control were analogous to those of normal rats injected with the complex high dose. The histopathological analysis also supported the above findings. These results show that complex has good antioxidant and therapeutic properties, which can help in treating and preventing CCl4-induced hepatotoxicity.