<p>Difluprednate is marketed as an emulsion due to its poor aqueous solubility. Emulsions are known to cause ocular discomfort and require frequent dosing to show therapeutic activity. Nanomicelles are well known to improve the solubility and permeation of water-insoluble drugs. Therefore, to enhance the water solubility and reduce the dosing frequency by improving difluprednate permeation across the cornea, we formulated nanomicelles. Difluprednate loaded nanomicelles (Dicel) was prepared by thin film hydration method and optimized using Box-Behnken design. The Dicel formulated had a particle size, polydispersity index, zeta potential and entrapment efficiency of 21.9&#xa0;nm, 0.15, -7.55&#xa0;mV and 75.4%, respectively. Transmission electron microscopy analysis showed spherical nanomicelles. The Dicel showed a sustained release profile for 48&#xa0;h. The difluprednate permeation across the cornea from Dicel was enhanced by twofold compared to commercially available emulsion. Also, it was found to be stable upon dilution with simulated tear fluid and was biocompatible. Further, Dicel improved the anti-inflammatory activity of difluprednate at one and two times a day administration compared to four times a day administration of difluprednate emulsion. The present study highlights the role of topical nanomicelles in delivering difluprednate, which is better than the existing marketed emulsion in the management of ocular inflammation.</p> Graphical Abstract <p></p>