The aim of the present study was to prepare a leflunomide (LFD) sustained release transdermal delivery system for the treatment of psoriasis. In this context, LFD-loaded nanoparticles (NPs) based on either neat chitosan (CS) or CS modified with [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SDAEM, a sulfobetaine zwitterionic compound) were initially prepared via ionotropic gelation and characterized in terms of in vitro dissolution, physicochemical, and antibacterial properties. Results showed that the use of the SDAEM-modified CS resulted in the formation of LFD-loaded NPs with improved wetting and solubilization properties, better in vitro dissolution profile characteristics (i.e., higher dissolution rate and extent), and improved (enhanced) antibacterial properties. The resultant LFD-loaded NPs were then embedded in suitable thin-film skin patches, prepared via spin-coating, utilizing two different biodegradable polyesters, namely methoxy polyethylene glycol-b-poly(L-lactide) (mPEG-b-PLA, at a ratio of 25/75 mPEG to PLA) and poly(lactic-co-glycolic acid) (PLGA at a ratio of 75/25 DL-lactide/glycolide copolymer). Results showed the formation of polymeric thin-films with no agglomeration (or trapped air) and uniform structure in all cases, while the LFD-loaded NPs were successfully embedded in the polymeric matrix. Analysis of the obtained in vitro dissolution profiles revealed a sustained release profile of the drug for up to approximately twelve days, while between the two proposed systems, the use of CS-SDAEM NPs (independently of the polyester type) was the most promising formulation approach.