The unsatisfied results of cancer therapy are caused by many issues and metastasis of cancer cells is one of the major challenge. It has been reported that inhibiting the SDF1/CXCR4 interaction can significantly reduce the metastasis of breast cancer cells to regional lymph nodes and lung. Herein, a nanogel system equipped with the FDA-approved CXCR4 antagonist AMD3100 was developed and evaluated for its combined antimetastatic and tumor targeting effects. Briefly, a bioreducible cross-linked dextrin nanogel (DNG) coated with AMD3100 was designed to possess multiple functions, including CXCR4 chemokine targeting, inhibition of tumor metastasis, and reduction-responsive intracellular release of doxorubicin (DOX) to reduce the cells proliferation. The in vitro results confirmed that the DOX-loaded AMD3100-coated dextrin nanogel (DOX-AMD-DNG) was more effectively taken up by 4T1 breast cancer cells than DOX-DNG and was significantly more cytotoxic to 4T1 cells than DOX-DNG. In biodistribution studies, the stronger fluorescence intensity of Cy7-AMD-DNG than Cy7-DNG further confirmed that AMD3100 mediated tumor targeting in vivo. AMD3100-coated DOX-DNG also exhibited a distinct antimetastatic effect and CXCR4 antagonistic activity by inhibiting CXCR4-mediated cell invasion in 4T1 and U2OS cells. Moreover, DOX-AMD-DNG displayed superior anticancer activity and antimetastatic effects in orthotopic breast cancer-bearing Balb/C mice. In summary, the multifunctional DOX-AMD-DNG can effectively target the tumor site and dually impede cancer progression and metastasis.