The use of poly lactic-co-glycolic acid (PLGA) microspheres is limited due to the low drug loading capacity and the shortage of surface functional groups. In order to overcome the shortcomings of pure PLGA carriers, chitosan (CS) is usually used to modify PLGA. To prepare a hollow chitosan (CS)-coated PLGA microsphere (MS) of paclitaxel (PTX) and to improve the drug-loading efficiency and anticancer efficiency as well as to reduce drug administration frequency, in this work, hollow PLGA microspheres with rough chitosan shell were prepared by the modified double-emulsion solvent evaporation method. Morphology analysis confirmed the successful preparation of the CS-PLGA-PTX with a rough surface and hollow internal structures. Due to the chitosan coating on PLGA microspheres, the particle size increased from 65.14 ± 14.36 μm to 73.46 ± 12.12 μm; the zeta potential increased from −17.96 ± 2.66 mV to 19.18 ± 1.64 mV. Drug loading efficiency increased from 7.36 ± 1.10% to 11.80 ± 0.22%, indicating that the hollow structure could provide enough hydrophobic space for PTX-loading. After being modified with chitosan, the initial burst release of PTX from microspheres decreased from 27.36 ± 3.03% to 18.68 ± 2.19% at pH = 7.4, only 9.91 ± 1.80% at pH = 5.5. Besides, the drug release behavior manifested that the rough chitosan shell could offer deep surface folds for fast degradation. The in vitro studies pointed to the prolongated anticancer activity of CS-PLGA-PTX; furthermore, the novel microspheres could induce the pro-apoptosis gene and protein expressions while lowering the drug resistance, causing extensive cancer cell apoptosis. In conclusion, the novel chitosan-coated PLGA microspheres with outstanding anticancer performance could serve as a promising treatment for liver cancer.