The ever-increasing chemoresistance of osteosarcoma (OS) has been observed in the recent decades, impeding OS therapeutic improvement and posing an urgency to exploit to the alternative and/or supplementary therapies for the optimization of OS chemotherapeutic regimen. Ferroptosis, a regulated cell death, has been identified as a natural anticancer mechanism as well as a synergist for chemotherapeutics in various cancers. Herein, we affirmed the tumor-suppressing properties of eriodictyol and illustrated that its antitumor effects might ascribe to the ferroptosis-inducing activity, in which eriodictyol could bind with BACH1 to repress the transcription and translation of GPX4 and eventually result in the GPX4-related ferroptosis. Further investigation found that eriodictyol could exhibit a synergistic effect with cisplatin, facilitating the antitumor effects of cisplatin. Lastly, through utilizing hollow mesoporous prussian blue nanocubes loaded with eriodictyol and cisplatin, we formed the ferroptosis-synergistic nanocomplexes to facilitate OS cells ferroptosis and cisplatin sensitivity. Through direct catalytic oxidation of unsaturated lipids, exogenous iron delivery, GSH exhaustion, and GPX4 transcriptional inhibition, this ferroptosis-synergistic nanocomplex could excellently enhance OS cells ferroptosis in both vitro and vivo, with no obvious organ injury observed. Therefore, our ferroptosis-synergistic nanocomplex may represent a promising alternative therapeutic strategy for OS patients.