The objective of the study was to formulate and evaluate a stable thermoreversible mucoadhesive nasal gel of Mirtazapine (MRT)-loaded aquasomes for depression treatment. One of the major drawbacks of commercial MRT is extensive removal by first-pass effect, which we try to avoid by nasal route. Aquasomes formulae were prepared by the co-precipitation sonication method and assessed for their particle size and loading efficiency. The formula with the minimum particle size and the highest loading efficiency was chosen for further measuring their zeta potential and investigating its internal structure using the transmission electron microscope (TEM). MRT-loaded aquasomes were incorporated into in situ nasal gel by the cold process by utilizing Poloxamer 407 and various mucoadhesive polymers and tested for clarity, pH, mucoadhesive strength, viscosity, MRT content, and in vitro MRT release. The formulations that showed the highest drug release were selected for stability studies at temperatures of 4±2°C and 25±2°C/60±5%RH. The chosen formula showed the smallest particle size of 219.3±0.9 nm and the highest loading efficiency of 82.6±2.8%. TEM images revealed an almost nano size spherical shape with acceptable zeta potential (-15.9 m V). Nasal gel characterizations were confirmed to be within permissible limits, such as drug content and gelling temperature, which were found to be 96.56 to 99.55% and 29.5–32.1°C, respectively. It was found that the tested formulae were physically stable during the period of storage. These results suggested that MRT-loaded aquasomes in situ gel was found to be a promising intranasal formulation for the management of depression.