Mirtazapine is a tetracyclic anti-depressant drug approved by USFDA to treat depression. It is a BCS class II drug with a low oral bioavailability of 50% due to first pass metabolism. Thus, the purpose of this research work was to enhance the bioavailability of the drug by enhancing its solubility by incorporating it in to niosomal vesicles loaded in to an in-situ gel to enhance its permeability across the biological membrane. Niosomes were prepared by thin film hydration method and optimized by using 32 full factorial design. Mirtazapine loaded niosomes were further incorporated in to an Poloxamer 407 and Carbopol 934 in-situ gel base. The vesicle size of all niosomal suspension batches ranged between 202-245 nm. The vesicle size of the optimized batch F5 was found to be 211.7 nm with PDI of 0.166. The zeta potential value of F5 was found to be 0.6 mV. The % EE of all niosomal batches was found to be in a range of 69.3% – 83.7% and the cumulative % release was found to be in a range of 75.2% – 84%. DSC, XRD studies were performed for pure drug and niosomal batch F5. All the gel formulations ranged between 17.3±0.03 sec to 27.3±0.03 sec. Gelling temperature was found to be in a range of 44oC±0.00 to 53oC±0.0oC and mucoadhesive results were found to be in a range of 10.3 ±0.023 to 14.5±0.060g. In-vitro drug release was found to be in a range of 68.3%-74.6%.