Huntington's disease (HD) is a progressive neurodegenerative condition characterized by a severe motor incoordination, cognitive decline, and psychiatric complications. However, a definitive cure for this devastating disorder remains elusive. Agmatine, a biogenic amine, has gain attention for its reported neuromodulatory and neuroprotective properties. The present study was designed to examine the influence of agmatine on the behavioral, biochemical, and molecular aspects of HD in an animal model. A mitochondrial toxin, 3-nitro propionic acid (3-NP), was used to induce HD phenotype and similar symptoms such as motor incoordination, memory impairment, neuro-inflammation, and depressive-like behavior in rats. Rats were pre-treated with 3-NP (10 mg/kg, i.p.) on days 1, 3, 5, 7, and 9 and then continued on agmatine treatment (5 - 20 µg/rat, i.c.v.) from day-8 to day-27 of the treatment protocol. 3-NP-induced cognitive impairment was associated with declined in agmatine levels within prefrontal cortex, striatum, and hippocampus. Further, the 3-NP-treated rats showed an increase in IL-6 and TNF-α and a reduction in BDNF immunocontent within these brain areas. Agmatine treatment not only improved the 3-NP-induced motor incoordination, depression-like behavior, rota-rod performance, and learning and memory impairment but also normalized the GABA/glutamate, BDNF, IL-6, and TNF-α levels in discrete brain areas. Similarly, various agmatine modulators, which increase the endogenous agmatine levels in the brain, such as L-arginine (biosynthetic precursor), aminoguanidine (diamine oxidase inhibitor), and arcaine (agmatinase inhibitor) also demonstrated similar effects exhibiting the importance of endogenous agmatinergic pathway in the pathogenesis of 3-NP-induced HD like symptoms. The present study proposed the possible role of agmatine in the pathogenesis and treatment of HD associated motor incoordination, and psychiatric and cognitive complications.