Nanotechnology is an emerging interdisciplinary revolution in several therapeutic areas over the last decade, including medicine, and the drug delivery system. The essence of this new technology features a significant impact within the field of diagnosis and drug delivery. We developed chitosan nanoparticles to entrap ciprofloxacin hydrochloride and evaluate for the first time the impact of this polymeric nano system on the targeted drug delivery to the pilosebaceous units, considering the sebaceous characteristics of skin affected by acne. One of the most appealing, dependable, and efficient methods for consistently providing regulated drug administration is transdermal drug delivery system. The current study's goal was to create ciprofloxacin hydrochloride-loaded gel nanoparticles in order to increase their permeability and facilitate drug release over a 12-hour timeframe. Ion-Gelation method is use for formulation of nanoparticles using chitosan as a polymer and TPP as crosslinking agent. The compatibility of drug and polymer is studied using FTIR spectroscopy and DSC method. There was no interaction observed by UV and FTIR study. The six different batches were prepared using different polymer and drug ratio. Impact of different formulation factors on crucial qualities including entrapment efficiency were studied using a full factorial design. Optimized formulation shown (+19.32) mV zeta potential and a mean particle size (189.8) nm. When compared to Ciprofloxacin Hydrochloride solution, its nanoparticles exhibited a considerable increase in transdermal penetration in ex-vivo diffusion study across isolated rat skin.