Background: Reactive oxygen species (ROS) is considered as ubiquitous and highly active chemicals that influence tendon integrity and orchestrate tendon repair. With significant recent advances in nanomaterials, cerium oxide nanoparticles (CeO₂ NPs) exhibit superoxide dismutase- and catalase-like activities. Herein, we introduced a therapeutic approach of CeO₂ NPs for Achilles tendinopathy (AT) healing. Methods: CeO₂ NPs were synthesized to examine their effect as ROS scavengers on AT healing in vitro and in vivo. The mRNA levels of inflammatory factors were evaluated in AT after CeO₂ NPs treatment in vitro. The mechanisms underlying CeO₂ NPs-mediated stimulation of NRF2 translocation and ERK signaling were verified through immunofluorescence and Western blot analysis. The efficacy of CeO₂ NPs was tested in an AT rat model in comparison with the control. Results: CeO₂ NPs not only significantly scavenged multiple ROS and suppressed ROS-induced inflammatory reactions but also protected cell proliferation under oxidative stress induced by tert-butyl hydroperoxide (TBHP). Moreover, CeO₂ NPs could promote NRF2 nuclear translocation for anti-oxidation and anti-inflammation through the ERK signaling pathway. In a rat model of collagenase-induced tendon injuries, CeO₂ NPs showed significant therapeutic efficacy by ameliorating tendon damage. Conclusion: The present study provides valuable insights into the molecular mechanism of CeO₂ NPs to ameliorate ROS in tenocytes via the ERK/NRF2 signaling pathway, which underscores the potential of CeO₂ NPs for application in the treatment of enthesopathy healing.