This study was aimed to optimize and formulate desvenlafaxine succinate loaded niosomal in-situ nasal gel for the treatment of depression. Desvenlafaxine succinate loaded niosomal in-situ gel was fabricated by Thin Film Hydration method also known as hand shaking method. The present study involves the fabrication, optimization and characterization of the niosomal in-situ gel. The formulations were fabricated to enhance the bioavailability of lipophilic drug, so the drug can cross the barriers present in the brain without any complications. The barriers present in the brain i.e. cerebro spinal fluid barrier, and blood brain barrier causes hindrance to molecules to permeate the brain but permit the lipophilic molecule to pass. The niosomes were optimized by 32 and each formulation was divided by 22 for the preparation of hydrogel 1%w/v and 1.5% w/v chitosan (for example- in formulation F1 22 is applied then it will further divided into two parts that is F1G1 and F2G2, 1%w/v and 1.5%w/v chitosan respectively). The particle size of the optimized formulation F1G2 was found 342.9nm through particle size analyzer. The TEM images of the optimized formulation showed the formulated niosomes vesicles. Maximum entrapment efficiency was found 83.7% of the optimized formulation. In-vitro release was performed for 8 hours and maximum release was 82.57 %. Zeta potential value of the optimized formulation F1G2 was -22.4Mv, which shows the stability.