Simvastatin (SMV), a cholesterol-lowering agent, has antioxidant and anti-inflammatory effects. Nevertheless, the oral use of SMV is linked with poor systemic bioavailability owing to its limited aqueous solubility and extensive first-passmetabolism. The aimof this study was to evaluate the feasibility of transdermal delivery of SMV using bile salt stabilized vesicles (bilosomes) for enhancing the anti-inflammatory potential of SMV. SMV-loaded bilosomes (SMV-BS) were prepared by the thin film hydration technique and optimized by 33 Box–Behnken design. The fabricated SMV-BS were assessed for vesicle size, entrapment efficiency (% EE) and cumulative drug release. The optimized formula was incorporated into HPMC gel and investigated for physical properties, ex vivo permeation, in vivo pharmacokinetic study and anti-inflammatory potential in inflamed paw edema rat model. The optimized SMV-BS showed vesicle size of 172.1  8.1 nm and % EE of 89.2  1.8%. In addition, encapsulating SMV within bilosomal vesicles remarkably sustained drug release over 12 h, compared to plain drug suspension. Furthermore, SMV-loaded bilosomal gel showed a three-fold enhancement in SMV transdermal flux, compared to plain drug suspension. Most importantly, the relative bioavailability of SMV-BS gel was ~2-fold and ~3-fold higher than those of oral SMV suspension and SMV gel, respectively. In carrageenan-induced pawedemamodel, SMV-BS gel induced a potent anti-inflammatory effect, as evidenced by a remarkable reduction in paw edema, which was comparable to that of the standard anti-inflammatory drug, indomethacin. Collectively, bilosomes might represent a plausible transdermal drug delivery systemthat could enhance the anti-inflammatory activity of SMV by boosting its skin permeation and its systemic bioavailability.