Purpose <p>Psoriasis is a chronic autoimmune inflammatory disease affecting the skin and joints, characterized by scaly and erythematous lesions. Tetrahydrocurcumin (THC), a metabolite of curcumin has potent anti-inflammatory properties but suffers from poor permeability and bioavailability when administered orally. The present study aimed to develop and evaluate a niosome-based thermosensitive in-situ gel for sustained and localized delivery of THC in psoriasis management.</p> Method <p>Nine niosome-based In-situ gels loaded with Tetrahydrocurcumin (marked F1-F9) were created with different amounts of the polymers poloxamer F127 and F68. The niosomes were characterized for particle size, encapsulation efficiency and drug loading. In-situ gels were evaluated for gelation time, viscosity, gelation temperature and In-vitro drug release. The optimized formulation (F5) was further subjected to in-vivo evaluation in albino mice with psoriasis. </p> Result <p>THC-loaded niosomes showed the particle size of 116.9±23 nm, their encapsulation efficiency was 94.7±11%, and the drug loading ratio was 85.23±09%. Among all formulations, F5 showed a 94.7% release rate over 24 hours, utilizing a non-Fickian diffusion mechanism, which provided the best in-vitro drug release profile. The optimized in-situ gel formulation took 54 ± 1.0 seconds to gel, solidified at 32.5 ± 1.7°C, and had a viscosity of 892 ± 13 cps. In-vivo activity confirms that F5 significantly reduced psoriatic lesions in albino mice.</p> Conclusion <p>The optimized niosome-based thermosensitive in-situ gel (F5) demonstrated sustained drug release, favourable physicochemical properties, and improved therapeutic efficacy against psoriasis. The novel drug delivery system holds promise for effective, localized psoriasis treatment.</p>