Purpose <p>The aim of the current study was to develop and evaluate the therapeutic potential of apocynin loaded pH-sensitive nanoparticles (APO-NPs) based transdermal hydrogel for management of rheumatoid arthritis (RA).&#xa0;</p> Methods <p>Slightly modified nanoprecipitation technique was used for preparation of polymeric nanoparticles. Optimization was done through design expert software. Optimized APO-NPs were loaded into carbopol-934 based hydrogel as final dosage form.</p> Results <p>Optimized APO-NPs formulation showed a minimum particle size 63.44&#xa0;nm, polydisperibility index 0.161, and zeta potential − 15mV, along with a maximum encapsulation efficiency 89<i>%. In-vitro</i> and ex vivo studies of APO-NPs based hydrogel were performed at pH 5.5 (pH of normal skin) and 6.8 (pH of inflamed joint) showed a pH-responsive sustained drug release and increased penetration in comparison to free APO based hydrogel. The stability studies of APO-NPs based hydrogel were performed to strengthen the potential use of the prepared formulation through transdermal route. Assessment and therapeutic efficacy of prepared pH-sensitive nanocarriers system was evaluated in chronic RA mice model. Parameters associated with chronic inflammation were investigated including behavioral changes, histopathological, and radiological x-rays images of joints of mice hand paws. In vivo study depicts improvement in the behavioral parameter, decline in synovial hyperplasia and bone structure restoration.</p> Conclusion <p>thus, the APO-NPs based transdermal hydrogel is a promising carrier system that can effectively manage RA.</p> Graphical Abstract <p></p>