The co-delivery of siRNA and therapeutic agents provides an effective method for cancer chemotherapy by avoiding drug resistance during the treatment. With a combination of ionic gelation and supercritical fluid technology, nanoparticle-embedded composite microparticles (CMPs) co-loaded with siRNA and paclitaxel (siRNA-PTX-CMPs) were successfully prepared. The results show that CMPs embedded with nanoparticles with a diameter of 50-100 nm exhibited a spherical shape and core-shell structure with a mean diameter of 323 nm. The encapsulation efficiency of siRNA in chitosan nanoparticles (CS NPs) was 96.97%. The drug load and encapsulation efficiency of PTX-loaded CMPs (5% dosage) were 1.40% and 27.95%, respectively; both these increased with an increase in dosage. It was found that no change had occurred in the functional groups of the components during the supercritical process, while the physical form of PTX had shifted to an amorphous state. In the cell experiments, the CMPs clustered around the nucleus after being taken up by the Bcap-37 cells. The results of the antitumor effect experiments revealed that the co-loaded siRNA-PTX-CMPs achieved a significantly better synergistic effect than single dosages, which indicated that the co-delivery system developed by the supercritical process could have potential in the application of cancer chemotherapy.