<p>To develop and optimise a daridorexant-loaded pH-sensitive in situ nasal gel for enhanced bioavailability and therapeutic efficacy in insomnia treatment.&#xa0;Daridorexant-loaded pH-sensitive in situ nasal gels were formulated using Carbopol 934P and HPMC K4M as gel-forming polymers. A 3² full factorial design was employed to optimise the formulation, with polymer concentrations as independent variables and gelation time and mucoadhesive strength as dependent variables. The optimised formulation was characterised for physical appearance, pH, viscosity, drug content, ex vivo permeation, and accelerated stability. In vivo pharmacokinetic studies were conducted in Sprague–Dawley rats to compare the optimised formulation with intravenous and intranasal solutions.&#xa0;The optimised formulation (F6) containing 0.22&#xa0;mg Carbopol 934P and 0.30&#xa0;mg HPMC K4M exhibited ideal gelation at nasal cavity pH (6.26 ± 0.05), rapid gelation time (26.8 ± 1.4&#xa0;s), and excellent mucoadhesive strength (3853.7 ± 112.8 dynes/cm²). Statistical analysis confirmed the significant influence of polymer concentration on formulation characteristics (<i>p</i> &lt; 0.001). The formulation demonstrated sustained drug release (84.8 ± 2.9% at 12&#xa0;h) and maintained stability under accelerated conditions with minimal changes in critical parameters (&lt; 5%). Pharmacokinetic studies revealed enhanced bioavailability (77.8% absolute bioavailability) compared to intranasal solution (52.9%), demonstrating a 1.47-fold improvement in relative bioavailability with extended plasma retention (MRT = 11.78&#xa0;h).&#xa0;The developed pH-sensitive in situ nasal gel significantly enhances daridorexant bioavailability while providing controlled release characteristics. This formulation offers potential clinical advantages, including reduced dosing frequency, improved sleep maintenance, and minimised morning residual effects for insomnia patients, warranting further clinical evaluation.</p> Graphical Abstract <p></p>