Background: Ketoprofen, a widely prescribed non-steroidal anti-inflammatory drug (NSAID), exhibits significant therapeutic efficacy in managing chronic inflammatory conditions; however, conventional oral administration is frequently associated with dose-dependent gastrointestinal toxicity, peptic ulceration, hepatic impairment, and cardiovascular risks, necessitating the development of safer, non-invasive transdermal delivery alternatives that circumvent first-pass hepatic metabolism and minimize systemic adverse effects (Brooks et al., 1991; Kumar et al., 2023). Objective: This study aimed to design, systematically optimize, and comprehensively evaluate ketoprofen-loaded transethosomal gel as an advanced nano vesicular transdermal delivery platform for sustained anti-inflammatory therapy. Methods: Ketoprofen transethosomes were prepared using thin film hydration technique incorporating soya phosphatidylcholine, Span 20 (edge activator), and ethanol (permeation enhancer). Systematic optimization investigated four critical variables—phospholipid: surfactant ratio, ethanol concentration, drug loading, and stirring time—with vesicle size, zeta potential, and entrapment efficiency as key responses. The optimized dispersion was incorporated into Carbopol 934-based gel and characterized for pH, viscosity, spread ability, extrudability, drug content, in-vitro release kinetics using Franz diffusion cells, and accelerated stability under refrigerated and ambient conditions. Results: The optimized formulation (F12: PC:Span 20 ratio 8:2, ethanol 10% v/v, drug 1.0% w/v, stirring 5 min) yielded nanometric vesicles (135.65 ± 5.25 nm) with high entrapment efficiency (76.65 ± 2.85%) and robust colloidal stability (zeta potential −39.98 ± 2.15 mV). The transethosomal gel demonstrated skin-compatible pH (6.8 ± 0.15), appropriate viscosity (3250 ± 125 cP), near-complete drug content (99.12 ± 1.85%), satisfactory spread ability (11.21 ± 0.85 g·cm/s), and excellent extrudability (187 ± 12 g force). In-vitro release exhibited biphasic profile with modest initial burst (~18% at 0.5 h) followed by sustained diffusion-controlled release, achieving 98.12 ± 2.45% cumulative ketoprofen liberation at 10 hours (best fit: Higuchi model, r² = 0.982). Conclusion: Ketoprofen-loaded transethosomal gel represents a scientifically sound, technically feasible, and clinically promising non-invasive platform for prolonged transdermal anti-inflammatory therapy, meriting further ex-vivo skin permeation studies and in-vivo pharmacodynamic evaluation.