A kind of core cross-linked poly(ethylene glycol)-graft-Dextran nanoparticles (CPD NPs) was prepared by a simple chemical cross-linking method for reduction and pH dual response drug delivery. The resultant CPD NPs are of homogeneous spherical structure with sizes from 69 ± 11 to 107 ± 18 nm. Doxorubicin (DOX) was then loaded into the CPD NPs in high efficiency, and showing typical reduction and pH dual responsive release profiles. The flow cytometric analysis and confocal laser scanning microscopy (CLSM) confirmed that the DOX-loaded CPD NPs could be internalized into cancer cell efficiently and release DOX in intracellular environment. Furthermore, cell cytotoxicity assays indicated that the CPD NPs had good biocompatibility toward both cancerous and normal cells, while the Dox-loaded CPD NPs exhibited significant inhibition of cell proliferation in various cancer cells. Therefore, this biocompatible CPD NP may have great potential for intracellular drug delivery in clinical cancer therapy.