Oxidative stress is known to impact neurological changes in the brain, predisposing an individual to brain disorders. This study explores the antidepressant potential of Mucuna pruriens (MP) through modulation of oxidative stress and cholinergic pathways, suggesting its potential as a therapeutic drug for mitigating depression induced by prolonged chronic mild stress (CMS) in Drosophila melanogaster. The efcacy of MP methanolic (MP-Meth) and aqueous (MP-Water) extracts was compared with two commercial antidepressants, Fluoxetine (FLX) and Amitriptyline (AMP). CMS was induced by exposing the fies to varying adverse conditions for 24 h. Fifty fies per group, with three replicates for each of the four regimens, were fed a standard feed and treated with 5 mg/ml/ body weight for 5 days. Survival rate analysis was done and the antidepressant effect of M. pruriens was evaluated by measuring biochemical parameters. Under heat stress, AMP reduced catalase activity (90.8%) and G-S-T levels significantly (96.5%), whereas MP-Meth had the most ameliorating effect on catalase activity (94.2%). MP-Water notably increased AchE activity under both heat (61.8%) and cold stress (97%). AMP showed the highest decrease in lipid peroxidation under heat stress (2.7%), and MP-Water had the most significant decrease under cold stress (19.3%). However, the analysis indicated that both extracts of MP have their peculiarity and efficacy across biochemical markers and stress variations. These findings emphasize the significance of novel, innovative treatments to address the multifaceted nature of depression, therefore, recommending comprehensive exploration of aqueous and methanol extracts from M. pruriens as promising therapeutics for enhancing depression management. Keywords Depression · Mucuna pruriens · Drosophila melanogaster · Chronic Mild Stress (CMS) · Antidepressant · Oxidative stress · Acetylcholinesterase