Psoriasis is a chronic inflammatory disease occurring due to a large cascade of molecular and biological processes. Pentoxifylline (PTX) has a profound anti-inflammatory activity and is clinically indicated in the management of psoriasis. PTX is highly hydrophilic and thus is permeation-limited to exert its action on the psoriatic lesions. Colloidal nanostructured lipid carriers (NLCs) is a boon for dermal drug delivery, but incorporation of hydrophilic medicaments is not only difficult to be achieved but is accompanied by suboptimal loading, erratic drug release and time-consuming. The present study was designed to develop NLCs incorporating PTX using the recently explored thin lipid film based microwave assisted rapid technique. Prior to the formulation, the crystal structure of PTX was analyzed by molecular modeling. NLCs formed within 4 min having a size of <200 nm, PDI of <0.250 and a surface charge <-28 mV. PTX was loaded and encapsulated to an extent of 10% and 90% in the NLCs. The drug flux was 4.848 μg/cm2/h at the end of 24 h with a detection of 14% in the receptor fluid indicating a higher retention of PTX within the skin (>84%). In addition, the PTX loaded NLCs were tested against imiquimod-induced psoriasis in mouse model. Histological examinations clearly showed a higher levels of remodeling of the skin layers compared to disease control. These results justify NLCs to be a promising topical delivery system for PTX during psoriasis and can be rapidly produced without the requirement of complex equipment and conditions.