Lung cancer remains one of the most prevalent and lethal malignancies worldwide. Oridonin (ORI) exhibits remarkable anti-lung cancer activity. Nevertheless, its clinical application in lung cancer therapy is severely hindered by poor solubility, fast metabolism, insufficient tumor penetration, and low selectivity. In this study, we developed a redox-responsive polymeric micelle (HA-cys-TOS) targeting the CD44 receptor to improve ORI bioavailability and tumor targeting. The polymer was synthesized via esterification and verified by 1H NMR. Our data showed that ORI@HA-cys-TOS exhibited good stability, biosafety and redox-responsive sustained release. Compared to HepG2 cells, ORI@HA-cys-TOS exhibited significantly enhanced internalization ability in A549 cells, likely due to HA binding to the CD44 receptor overexpressed on A549 cells. Unexpectedly, the enhanced targeted accumulation of ORI@HA-cys-TOS micelles in vivo was also observed in both subcutaneous and in situ lung cancer tissues. In vivo and in vitro antitumor studies demonstrated that ORI@HA-cys-TOS micelles exhibited significantly greater antitumor activity compared to free ORI. Notably, no side-effects were observed during the 21 days experimental period. This study provides an experimental basis for advancing ORI toward clinical personalized lung cancer therapy by targeting CD44 and responding to the tumor redox microenvironment.