<p>The oral route for Captopril (CAP) has limited intestinal absorption and has a short half-life. Hence, a transdermal delivery of CAP with a sustained release formulation may be beneficial. The pH-sensitive CAP nanoparticles (CAP-NPs) with a size of 153 were developed using Eudragit S 100 (EuS 100) through nanoprecipitation method. Structural analysis of Nanoparticles (NPs) demonstrated that CAP had been successfully loaded into NPs. These CAP-NPs have a percentage yield of more than 80% and entrapment efficiency (EE) of 88 ± 0.51%. CAP-NPs were successfully loaded into a hydrogel with eucalyptus oil to increase penetration. The hydrogel showed a pH value of 5.77 ± 0.05, a drug content of 89 ± 0.92%, spreadability of 356.65 ± 0.54 mm², and its rheological interpretation showed a shear thinning property. In vitro investigations of the CAP-NPs loaded hydrogel revealed the successful release of CAP (over 73%) at pH 7.4 for 72&#xa0;h and showed high drug permeation of 1538 ± 14.4&#xa0;µg/cm²through mice skin. CAP-NPs loaded hydrogel improved skin tolerability while the stability studies demonstrated the efficacy of both CAP-NPs and CAP-NPs loaded hydrogel during their shelf life. Thus, it may imply that this innovative hydrogel based on pH-sensitive nanocarriers has the potential to deliver CAP transdermally.</p> Graphical Abstract <p></p>