Cisplatin (DDP), a frontline chemotherapeutic agent in osteosarcoma (OS) treatment, is frequently paired with other compounds to enhance its therapeutic potency. Cardamom (CAR), a natural flavonoid, exhibits significant inhibitory effects on human OS cells while minimizing toxic side effects. In this study, we combined CAR and DDP to treat OS, revealing that the DDP/CAR combination synergistically inhibits the growth of human OS cells in vitro and in vivo. Network pharmacological analysis indicated that mammalian target of rapamycin (mTOR) may be an important cross-target for DDP/CAR combination. Notably, this combined treatment significantly reduced mTOR phosphorylation and elevated autophagy levels within OS cells. At the mechanistic level, the DDP/CAR regimen enhanced apoptosis and compromised the viability of OS cells by triggering autophagy. This impact was attenuated by the use of the mTOR activator MHY and the autophagy inhibitor hydroxychloroquine (HCQ). Furthermore, in DDP-resistant cell lines, CAR was able to mitigate DDP resistance by bolstering autophagy levels. In general, our results suggest that CAR bolstering autophagy levels DDP against OS cells through the induction of mTOR-mediated autophagy.