Huntington's disease (HD) is characterized by cognitive and psychiatric impairment caused by neuronal degeneration in the brain. Several studies have supported the hypothesis that oxidative stress is the main pathogenic factor in HD. The current study aims to determine the possible neuroprotective effects of nicotinamide on 3-nitropropionic acid (3-NP) induced HD. Male Wistar albino rats were divided into six groups. Group I was the vehicle-treated control, group II received 3-NP (20 mg/kg, intraperitoneally (i.p.) for 4 days, group III received nicotinamide (500 mg/kg, i.p.). The remaining groups received a combination of 3-NP plus nicotinamide 100, 300 or 500 mg/kg, i.p. respectively for 8 days. Afterward, the motor function and hind paw activity in the limb withdrawal were tested; rats were then euthanized for biochemical and histopathological analyses. Treatment of rats with 3-NP altered the motor function, elevated oxidative stress and caused significant histopathological changes in the brain. The treatment of rats with nicotinamide (100, 300 and 500 mg/kg) improved the motor function tested by locomotor activity test, movement analysis, and limb withdrawal test, which was associated with decreased oxidative stress markers (malondialdehyde, nitrites) and increased antioxidant enzyme (glutathione) levels. In addition, nicotinamide treatment decreased lactate dehydrogenase and prevented neuronal death in the striatal region. Our study, therefore, concludes that antioxidant drugs like nicotinamide might slow progression of clinical HD and may improve the motor functions in HD patients. To the best of our knowledge, this study is the first to explore the neuroprotective effects of nicotinamide on 3-NP-induced HD.