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Chemoresistance remains a major clinical challenge in osteosarcoma, primarily driven by inefficient drug delivery and the evasion of cell death. Here, a multifunctional poly(β-amino ester) (pBAE)-based therapeutic delivery system was developed for simultaneous codelivery of small interfering RNA (siRNA) and doxorubicin (DOX) to drug-resistant osteosarcoma cells. The system significantly enhanced siRNA transfection within 4 h and showed substantially enhanced cytotoxicity compared with free DOX at equivalent concentrations. Mechanistically, pBAE degraded in the acidic tumor microenvironment, facilitating siRNA and DOX release, which synergistically modulated apoptotic and pyroptotic signaling to induce cell death. In vivo studies in osteosarcoma-bearing mice demonstrated that pBAE-based treatment markedly suppressed tumor growth, reducing tumor volume by approximately 70% without significant adverse effects. This study presents a therapeutic strategy centered on the "enhanced delivery-induced cell death" paradigm, effectively overcoming osteosarcoma chemoresistance and designing multifunctional nanodelivery systems for cancer therapy.