The purpose of this work was to create and assess Lornoxicam (LOR) loaded Novasomes (Novas) for the efficient treatment of ulcerative colitis. The study was performed using a 2(3) factorial design to investigate the impact of several formulation variables. Three separate parameters were investigated: Surface Active agent (SAA) type (X(1)), LOR concentration (X(2)), and SAA: Oleic acid ratio (X(3)). The dependent responses included encapsulation efficiency (Y(1): EE %), particle size (Y(2): PS), zeta potential (Y(3): ZP), and polydispersity index (Y(4): PDI). The vesicles demonstrated remarkable LOR encapsulation efficiency, ranging from 81.32 +/- 3.24 to 98.64 +/- 0.99%. The vesicle sizes ranged from 329 +/- 9.88 to 583.4 +/- 9.04 nm with high negative zeta potential values. The release pattern for Novas' LOR was biphasic and adhered to Higuchi's model. An in-vivo study assessed how LOR-Novas affected rats' acetic acid-induced ulcerative colitis (UC). The optimised LOR-Novas effectively reduced colonic ulceration (p < 0.05) and reduced the inflammatory pathway via inhibiting Toll-like receptor 4 (TLR4), Nuclear factor kappa beta (NF-kappabeta) and inducible nitric oxide (iNO). At the same time, it elevated Silent information regulator-1(SIRT-1) and reduced glutathione (GSH) colon contents. Thus, the current study suggested that the formulation of LOR-Novas may be a viable treatment for ulcerative colitis.