Dietary supplementation of functional foods has been established for cognitive enhancement. Fireweed (Crassocephalum crepidioides) is a notable vegetable reported in folklore for its anti-neurodegenerative property, with paucity of information on its mechanism of action using a cell-based system. This study sought to evaluate the effect of fireweed leaf dietary inclusion (FDI) on some biochemical indices of neurodegeneration of a fruit fly (Drosophila melanogaster) model of Alzheimer's disease (AD). Transgenic (modeled for AD) and Harwich (the wild control) fruit fly strains were used, and were exposed separately to 0%, 0.31%, 0.63%, 1.25%, and 2.50% FDI for 14 days. Survival rate, locomotive performance, and short-term memory index of the flies were assessed. Thereafter, the flies' homogenates were prepared and used for the determination of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase (MAO), catalase, superoxide dismutase, and glutathione S-transferase activities, total thiol, reactive oxygen species (ROS), and thiobarbituric acid reactive species (TBARS) levels. The result revealed that AD flies treated with FDI had 70%-80% improved survival rate and behavioural performance. Furthermore, AChE, BChE, and MAO activities were significantly (p < 0.05) inhibited, while antioxidant status was also boosted in the AD flies comparable with the wild control flies. In conclusion, the modulation of cholinesterases and monoamine oxidase activities as well as oxidative stress biomarkers could be among the neuroprotective mechanisms of fireweed leaf. These effects could be attributed to the abundant polyphenols and dietary fibers present.Hence, its use in folklore for the management of neurological disorder is justified.