Abstract Lornoxicam is a Biopharmaceutics Classification System (BCS) Class II drug prescribed for rheumatoid arthritis and osteoarthritis. It is potent analgesic and anti-inflammatory agent but has poor aqueous solubility (pka 4.7) that reduces its oral absorption and pharmacological effect. The aim of the present study was to formulate polymeric nanoparticles of lornoxicam with increase aqueous solubility and better anti-inflammatory effect using anti-solvent precipitation method. A 22 full factorial design was used taking chitosan and soluplus® as independent variables whereas average particle size (z-average), % drug release and polydispersity index (PDI) as dependent variables. Four formulations fabricated, subjected to dynamic light scattering, in-vitro drug release (pH 1.2 HCl and pH 6.8 phosphate buffer), PDI and encapsulation efficiency. The results showed good characteristic features of trial formulations in nanodimensions. The formulation (F1) containing chitosan (80mg) and soluplus® (4mg) was selected as an optimized formulation due to less z -average (198.7±2.95nm) and PDI (0.225±0.01), stable zeta potential (-16.87±1.95) and maximum % drug release in pH 6.8 phosphate buffer (89.14±0.67%; p<0.05) comparatively to pure lornoxicam. The optimized formulation followed first order kinetics based on high R2 (0.98), low AIC (48.79) and high MSC (3.64). The drug release mechanism was studied by Higuchi model that showed diffusion and erosion pattern with good correlation coefficient. Atomic force microscopy, Fourier transform Infrared, Thermogravimetric differential scanning calorimetry and X-ray powder diffraction characterization of the optimized formulation revealed its spherical shape, stable and semi crystalline structure and well polymeric encapsulation. The F1 formulation exhibited dose dependent results at 0.1mg/kg (56.55%;p< 0.005) and 0.3mg/kg (81.11%;p<0.005) with IC50 0.06mg/kg comparatively to pure lornoxicam for the same and higher doses (1mg/kg) respectively (p<0.005). Thus, the chitosan and soluplus® in combination at higher levels appeared to be best combination in formulating lornoxicam nanoparticles that successfully enhanced aqueous solubility, % drug release and pharmacological effect. In-vivo human studies of lornoxicam nanoparticles, its role in arthritis model are recommended for future researches.