<p>The objective of this study is to develop and optimize an emodin-loaded mucoadhesive in situ nasal gel for enhanced brain targeting in migraine treatment, addressing the limitations of conventional delivery systems. Thermosensitive in situ gels were prepared using Poloxamer 407 and almond gum. Formulations were characterized for pH, gelation temperature, viscosity, drug content, and mucoadhesive strength. A 3² full factorial design was employed to optimize the formulation with almond gum and Poloxamer 407 concentrations as independent variables. The optimized formulation was evaluated for ex vivo permeation across goat nasal mucosa, stability, and therapeutic efficacy in a nitroglycerin-induced migraine model. The optimized formulation (AF5) containing 2.75% almond gum and 20% Poloxamer 407 exhibited ideal gelation temperature (33.8&#xa0;°C), gelation time (65&#xa0;s), and mucoadhesive strength (6482 N/cm²). The statistical optimization showed excellent agreement between predicted and experimental values (error &lt; 0.07%). Ex vivo studies revealed superior permeation (93.97% over 8&#xa0;h) with steady-state flux of 123.56&#xa0;µg/cm²/h. In vivo study demonstrated significant amelioration of migraine symptoms, with locomotor activity restored to 92% of normal levels and comparable efficacy to sumatriptan. The formulation normalized neuroinflammatory markers, reducing nitric oxide (55.5%), MDA (57.3%), and CGRP (53.6%) while increasing antioxidant markers GSH (68.1%) and SOD (57.3%) compared to the migraine control. The optimized emodin-loaded mucoadhesive in situ nasal gel demonstrates significant potential for migraine management with enhanced brain targeting, rapid symptom relief, and improved neurochemical modulation. This novel delivery system offers the advantages of non-invasive administration, prolonged nasal retention, and reduced systemic side effects, warranting further clinical investigation for translation into an effective migraine therapy.</p>