This study explores the potential of nanoformulating bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI) used to treat major depressive disorder (MDD), into niosomal vesicles to enhance its efficacy and reduce adverse effects. Bupropion, while effective, can cause seizures and liver failure with regular use and overdose. The research aimed to improve the drug's therapeutic effect at lower doses by enhancing its brain penetration through the blood-brain barrier (BBB). The study used a thin film hydration method to synthesize and optimize niosomes with different surfactants (Span 20, 40, and 60) and cholesterol. The optimized formulation, Bup@N20C, showed minimal toxicity and sustained release of bupropion in artificial cerebrospinal fluid (ACSF). Behavioral studies in adult zebrafish models of depression revealed that Bup@N20C improved exploration activity and reduced irregular movements, surpassing the positive control group and comparable to the standard treatment group. The research highlights the potential of niosomal formulations of bupropion as a promising delivery system for improving mood and reducing depression-like behavior.This study explores the potential of nanoformulating bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI) used to treat major depressive disorder (MDD), into niosomal vesicles to enhance its efficacy and reduce adverse effects. Bupropion, while effective, can cause seizures and liver failure with regular use and overdose. The research aimed to improve the drug's therapeutic effect at lower doses by enhancing its brain penetration through the blood-brain barrier (BBB). The study used a thin film hydration method to synthesize and optimize niosomes with different surfactants (Span 20, 40, and 60) and cholesterol. The optimized formulation, Bup@N20C, showed minimal toxicity and sustained release of bupropion in artificial cerebrospinal fluid (ACSF). Behavioral studies in adult zebrafish models of depression revealed that Bup@N20C improved exploration activity and reduced irregular movements, surpassing the positive control group and comparable to the standard treatment group. The research highlights the potential of niosomal formulations of bupropion as a promising delivery system for improving mood and reducing depression-like behavior.