Purpose <p>The purpose of the present work is to improve the brain uptake by developing and characterizing an in-situ nasal formulation of Edaravone nanosuspension.</p> Methods <p>A quality-by-design approach was comprehended for the understanding of the influence of formulation and process parameters on the quality aspects. The solvent-antisolvent method was employed for the fabrication of nanosuspension. In the study, the influence of various process and formulation parameters on the particle size and % drug content were investigated. Optimization was carried out using response surface methodology. To improve the stability of the nanosuspension, lyophilization using trehalose was performed. Lyophilized powder was incorporated into in-situ nasal gel.</p> Results <p>The formulation with a 1:1 drug-polymer ratio and the lowest Tween 80 concentration was found to meet the criteria for an optimum formulation. The lyophilized powder of nanosuspension was subjected to the various physical characterizations showed the inclusion of drug molecule into the polymer. Lyophilized powder containing in-situ formulation was demonstrated to have adequate mucoadhesion, prolonged in vitro release, 10% increment in nasal permeation flux and good rheological properties. In-vivo studies revealed 12% increment in brain bioavailability and 9% increment in brain Cmax in comparison with marketed injectable formulation.</p> Conclusion <p>This research highlights the depth of understanding achieved through a well-designed study based on the QbD approach.</p>