Introduction: Amitriptyline Hydrochloride faces challenges related to extensive hepatic first-pass metabolism, limiting its bioavailability. Objectives: The study aimed to formulate and evaluate thermoreversible in-situ nasal gel formulations of Amitriptyline Hydrochloride. Methodology: Thermally triggered in-situ nasal gels were prepared using Poloxamer 407 as the gelling polymer and HPMC K4M as the mucoadhesive polymer. Formulations underwent comprehensive characterization, including clarity assessment, pH determination, gelation temperature measurement, viscosity analysis, and determination of drug content. Mucoadhesive strength, gel strength, In-vitro and Ex-vivo drug release studies, and histopathological examination were conducted. Results: Formulations exhibited clear appearances with gelling temperatures ranging from 39°C to 32°C. Drug content exceeded 78.33% across all formulations. Viscosity increased with temperature and polymer concentration. pH values fell within the nasal physiological range (4.7-5.9). The optimized formulation (F4) demonstrated 96.64% In- vitro drug release in 8 hours and 87.52% Ex-vivo drug release. Histopathological examination revealed no adverse effects. Conclusion: Thermoreversible in-situ nasal gels offer a promising drug delivery strategy for Amitriptyline Hydrochloride, circumventing hepatic first-pass metabolism and enhancing drug bioavailability. The developed formulations exhibit favorable properties and show potential as a therapeutic option for depressive disorders.