<p>In this study, the preparation of pH- and reduction-responsive doxorubicin (DOX)-loaded hyaluronate acid-F127 supramolecular hydrogels (DOX@Gels) with targeting ability due to the incorporation of hyaluronic acid is described. By combining Pluronic F127-modified hyaluronic acid (HA-F127), disulfide-modified β-cyclodextrin, α-cyclodextrin, and DOX, hydrogels were constructed through host–guest complexation and hydrogen bonding interactions, and a tailored platform for targeted drug delivery was provided. The chemical composition and rheological properties were comprehensively analyzed. Considering the controlled complexation between DOX and the hydrogel skeleton and the ability of HA to target cancer cells, controlled drug release from the hydrogel G[15,5,5] was investigated under various conditions in vitro. The cumulative amount of DOX released from hydrogel G[15,5,5] showed superior pH- and reduction-controlled release behavior. These results were likely caused by the HA-F127 ester bonds cleavage in acidic environments and the S‒S bond cleavage within the hydrogel networks in the presence of glutathione. Furthermore, the DOX release kinetics were analyzed using Higuchi and Korsmeyer-Peppas models. The results demonstrated that the experimental data was effectively fit with these two models, and the data fitted by using Korsmeyer-Peppas also indicated nonFickian diffusion kinetics of the DOX being released from hydrogels. Owing to the ability of HA to target SKOV-3 cells, the cytotoxicity experiments revealed that DOX@G[15,5,5] exhibited more significant anticancer effects than free DOX. Consequently, DOX@Gels containing HA have emerged as promising candidates for the targeted delivery and release of anticancer drugs.</p>