A general strategy was developed to fabricate the chitosan-based micelles as smart drug delivery system (DDS) for anti-cancer drug doxorubicin (DOX), via modulating the feeding ratio of PEG (PEG2000-CHO) and molecular weight of chitosan. Typically, benefiting from the solubility of chitosan in media with different pH values as an “off-on” switch, the DOX/CS100K-PEG2 micelles possess spherical core with a narrow dispersed diameter of 64 nm and regular shell with a thickness of 14 nm in pH 7.4 PBS. Interestingly, the DOX/CS-PEG micelles exhibited drug leakage-free behavior in a physiological environment, with a cumulative release ratio of only 2.32% under pH 7.4 PBS, while achieving rapid drug release and a cumulative release ratio of 72.76% in the intracellular microenvironment. Moreover, the micelles transformed into the water-soluble CS100K-PEG2 after the pH-triggered intracellular release of DOX, and it makes them easy to be biodegraded and eliminated by metabolic system. As revealed by MTT assays and CLSM images, DOX could be efficiently and rapidly transported into cell nuclei of tumor cells and showed significant cell inhibition. The simple fabrication and excellent properties make them intelligent and favorable on-demand DDS in cancer treatment.