Huntington's disease (HD) is an incurable, chronic, progressive, and autosomal-dominant genetic neurodegenerative disorder manifested by abnormal involuntary and voluntary movements, cognitive, and psychiatric disruptions linked with corticostriatal neuronal loss. HD is one of the deadliest diseases commonly affecting older people and the present treatment offers only systematic relief without hindering the onset or ameliorating the disease. 3-Nitropropionic acid (3-NP) treatment mimics HD pathology via striatal degeneration leading to motor and cognitive anomalies. Therefore, striatal neurodegeneration involving a 3-NP model using transgenic animals and expressing mutant proteins is commonly used in preclinical investigations in order to elucidate HD-pathology and explore possible anti-HD therapeutics. In this present review, a number of plant-derived natural products are reported on the basis of their ability as disease-modifying agents active against HD-pathology in various neurotoxic and transgenic animal models via biochemical and molecular modulations of different signaling pathways commonly involving mitochondrial and oxidative stress. Anti-HD activity has been observed for α-mangostin, astragalan, berberine, celastrol, curcumin, galantamine, ginsenosides, hesperidin, lycopene, melatonin, onjisaponin b, protopanaxtriol, resveratrol, S-allylcysteine, sesamol, spermidine, vanillin, etc. These natural compounds alleviated disease pathology via retarding motor dysfunction, autophagy, mitochondrial dysfunction, lipid peroxidation, neuroinflammation, striatal toxicity, and also by promoting antioxidation, mutant protein degradation, motor and cognitive functions, behavioral improvement via modulation of biochemical and molecular signaling pathways, viz., Keap1-Nrf2-ARE pathway, MAPKs and NF-κB pathways, ERK pathway, etc. Moreover, the complex nature and possible synergism of polyherbal formulations containing phytochemicals against the multifactorial nature of HD-pathogenesis have also been discussed. However, very few systematic structure–activity relationship studies have been performed in order to explain the underlying mechanism of action of the natural products against neurodegenerative disorders, such as HD. Limited animal models and overdependence on cellular models are considered as major constraints in evaluating anti-HD natural products. However, the advent of HD transgenic models expressing mutant proteins may facilitate the routine screening of probable anti-HD natural therapeutics besides explaining HD-pathogenesis and more efficacious treatment strategies.