Naproxen (NAP) is commonly used for pain, inflammation, and stiffness associated with arthritis. However, systemic administration is linked with several gastrointestinal tract (GIT) side effects. The present work aims to prepare and evaluate NAP nanoparticulate shells of chitosan (CS) and carrageenan (CRG) loaded into a Carbopol 940 (Ca-940) gel system with unique features of sustained drug delivery as well as improved permeation through a topical route. Moreover, this study aims to evaluate its ex vivo, histopathological, and in vivo anti-inflammatory activity in albino Wistar rats. The percentage of ex vivo drug permeation patterns in the optimized formulation (No) was higher (88.66%) than the control gel (36.195%). Oral toxicity studies of developed nanoparticles in albino rabbits showed that the NAP-loaded CS/CRG are non-toxic and, upon histopathological evaluation, no sign of incompatibility was observed compared to the control group. A In Vivo study showed that the optimized gel formulation (No) was more effective than the control gel (Nc) in treating arthritis-associated inflammation. The sustained permeation and the absence of skin irritation make this novel NAP nanoparticle-loaded gel based on CS/CRG a suitable drug delivery system for topical application and has the potential for improved patient compliance and reduced GIT-related side effects in arthritis.