Effective cancer therapy usually requires the assistance of well-designed drug carriers. In order to increase the drug accumulation to tumor tissue as well as to reduce the side effects of drug carriers, the hybrid drug delivery system (DDS) was developed by integrating folic acid (FA) and a metal-organic framework (MOF). The anticancer drug doxorubicin (DOX) was preloaded into the MOF nanoparticles during the synthesis process of the MOF nanoparticles. After surface modification with FA, the resulting FA/MOF/DOX nanoparticles were capable of serving as a biocompatible osteosarcoma targeting a DDS to enhance the chemotherapy of osteosarcoma. The dynamic light scattering method revealed that the obtained FA/MOF/DOX nanoparticles were particles with a size around 100 nm. Moreover, FA/MOF/DOX nanoparticles could enhance the delivery efficacy of DOX into MG63 (human osteosarcoma) cells as compared to FA free nanoparticles (MOF/DOX), in which a folate receptor (FR) might be involved. It was worth mentioning that in vitro [methylthio tetrazole (MTT) study in the MG63 cells] and in vivo (anticancer study in the MG63 xenograft model) assays both revealed that FA/MOF/DOX nanoparticles possessed stronger anticancer capability than free DOX or MOF/DOX nanoparticles.