Intranasal drug delivery system has been proposed as an alternative delivery system to target agomelatine (AGO) to the brain and improving its bioavailability. Mucoadhesive egg lecithin nanoemulsions were optimized using D-optimal design and by investigating the effect of four independent variables: oil concentration (A), chitosan concentration (B), type of oil (C) and egg lecithin: oil (D). The responses of globule size, polydispersity index, zeta potential and drug content were evaluated. The optimized agomelatine mucoadhesive nanoemulsion (AGO MNE) with a desirability value of 0.856 was subjected to further investigations for mucoadhesion, in vitro diffusion, transmission electron microscopy and in vivo biodistribution. It showed significantly successful distribution to the brain, the optimized AGO MNE intranasal gave a brain targeting efficiency (BTE) of 278.71% indicating increased drug brain targeting by the nasal route compared with the intravenous route. Additionally, the optimized AGO MNE by intranasal had a direct transport percentage (DTP) of 64.109%, which indicates a significant contribution of the direct nose-to-brain pathway in the brain drug delivery. The study proposed egg lecithin mucoadhesive nanoemulsion as a successful and promising strategy to directly and efficiently deliver drug to the brain.