Doxorubicin (DOX) is a powerful chemotherapy drug for cancer treatment, especially in patients with advanced cancer. However, clinical use of DOX remains challenging due to its widespread drug resistance and severe cardiotoxicity. Here, we developed a novel DOX-loaded natural hydrogel microparticle by using microfluidic electrospray technology. The designed carboxymethyl cellulose-based hydrogel microparticles were cross-linked by iron ions and showed a sustained drug release. The animal experiments revealed that DOX-loaded microparticles had good biocompatibility when locally injected into tumor-bearing mice, and could enhance the effect of chemotherapy and effectively inhibit tumor growth without obvious toxicity. These features indicated that the natural biomass-based hydrogel microparticles are highly promising for chemotherapy drugs delivery and provide a platform for local therapy.