To increase the accumulation of nanocarriers at the tumor site and reduce premature drug leakage, we fabricated alginate modified superparamagnetic iron oxide nanoparticles (SPIONs) with magnetic targeting capability for pH-responsive release of the anticancer drug doxorubicin (DOX) in tumor-cell microenvironments. The drug loading content (DLC) of SPION-4 was as high as 48.98% with a stable size of 135 nm, whereas the DLC of SPION-2 (amine-functionalized SPIONs as the control) was 7.58%. The in vitro release studies revealed that the acidic environment (pH 6.5 and pH 5.0) triggered the effective release of DOX from DOX-loaded SPION-4 twice and thrice as much as the neutral condition (pH 7.4) after 10.7 h, respectively. These nanocarriers exhibited good cytocompatibility towards both normal cells (LO2) and cancer cells (HepG2), but higher cytotoxicity against HepG2 cells for DOX-loaded SPION-4 than that against LO2 cells could be observed due to the effects of an additional magnet and the acidic microenvironment of cancer cells, which greatly improved the cellular uptake of magnetic nanoparticles and released more DOX in the cytoplasm and nucleus. The in vivo biodistribution and anti-tumor efficacy demonstrated that DOX-loaded SPION-4 under an external magnetic field could obviously increase the DOX concentration in tumor tissues to remarkably inhibit tumor growth and significantly reduce side effects of free DOX. Therefore, this work suggested that these SPION-4 nanoparticles may be a potential carrier to deliver chemotherapeutic agents in anti-tumor treatment.