Objectives: Baclofen is a skeletal muscle relaxant with an anti-inflammatory effect. The current market products of baclofen are oral tablets and intrathecal injection which cause many undesirable systemic side effects. This study aimed to formulate topical formula of baclofen to decrease systemic side effects. Topical drug delivery systems formulated as nanoparticles (NPs) enhanced the low drug release and the low bioavailability of the traditional gels. This occurs by prolonging the contact time and increasing the permeability of the drug through the skin. Methods: In this study, formulae of the baclofen-loaded Eudragit ® RL100 (ERL) NPs were prepared by nanoprecipitation method. Polyvinyl alcohol (PVA) was added as a stabilizer. The NPs were characterized by measuring their particle size, polydispersity index (PDI), zeta potential, and entrapment efficiency percent (EE %) values. Their spherical morphology was confirmed using transmission electron microscopy (TEM). Viscosity was also measured. In vitro release and permeation studies were done to evaluate the release of the drug from the NPs gel and the permeability of the drug through the skin. The results were compared with formulated baclofen traditional gel. Results: ERL concentration and organic phase ratio were the main factors affecting the NPs formulation. A decrease in the particle size was observed with an increase in ERL% while the smallest particle size was observed with formulae containing organic phase (acetone: methanol) in the ratio of 1: 3. The highest EE% was observed with the highest ERL concentration and the same organic phase ratio (acetone: methanol 1:3). Formulae B3, B6, B9 were selected for their most promising results. Their particle size was 187.4 ±2. 81, 126.3 ±1.47, 120.0 ±1.06 nm and their EE% was 78.9 ±0.30, 83.3 ±0.26, and 86.6 ±1.12, respectively. The percentages of the drug released from the selected formulae as well as the percentage of the permeated drug were significantly higher than that of the baclofen traditional gel. Conclusion: ERL NPs were capable of releasing baclofen and improving its permeability through the skin so it may be considered as a suitable promising alternative drug delivery system.