Polymeric nanoparticles (NPs) are interesting drug carriers for dermal application and drug targeting to certain skin structures. NP interactions with diseased skin and the associated benefits and risks have been hardly explored. Today, we study the behavior of polymeric NPs for selective drug delivery to inflamed skin. Neutral, cationic, and anionic NPs of nominal diameters around 100 nm were administered to an experimental dithranol-induced dermatitis inflammation model in mice ears. The results showed that the surface charge had an important influence on the penetration and accumulation tendency in the inflamed skin compared with the neutral and cationic (2.8 ± 0.3%, 2.1 ± 0.2%, and 1.9 ± 0.3% for anionic, neutral, and cationic particles, respectively). Confocal laser scanning microscopy showed that all particles were accumulated in the inflamed pilosebaceous units. Betamethasone-loaded NPs showed that both charged particles were therapeutically more efficient than the neutral ones. Treatment with anionic and cationic particles led to the reduction of the inflammatory enzyme alkaline phosphatase activity by 50.7 ± 2% and 57.7 ± 5%, respectively, in comparison with the inflamed control. Noncharged particles had a lower therapeutic impact where the activity was only reduced by a factor of 75%. Histological sections examination had also confirmed these results. Therefore, it was concluded that the presence of charge could enhance skin-NPs adhesion and interaction leading to higher therapeutic effect on inflamed skin.