A major challenge in pharmaceutical research is effective targeting strategies to their sites of action. Emerging knowledge and the current progress in nanotechnology based delivery systems has opened up exciting ways towards successful targeted nanodelivery systems. For cancer therapy, nanoparticle-based drug formulations hold several advantages over free drugs, including improved pharmacokinetics, enhanced tumor accumulation, reduced systemic exposure and side effects and better patient compliance. The goal of this study was to validate the in vivo targeting potential and evaluate the combinatorial therapeutic potential of novel Annexin A2 (AnxA2) antibody-conjugated curcumin loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (AnxA2-CPNP) against metastatic breast cancer. As a first step, we demonstrated that the cell-surface expression of AnxA2 is increases during breast cancer progression with very high expression in highly malignant cancer cells and basal expression in non-malignant cells. This confirmed AnxA2 as an excellent target for targeting our curcumin nanoparticles. Our results indicate that AnxA2-CPNP showed increased uptake in highly metastatic breast cancer cells than untargeted nanoparticles due to the differential AnxA2 expression. Cell viability, plasmin generation and wound healing assays reveal that AnxA2-CPNPs effectively inhibited cell proliferation, invasion and migration, key elements for cancer growth and metastasis. Further, angiogenesis assay illustrated that AnxA2-CPNPs decreased the formation of tube capillaries, thus inhibiting neoangiogenesis, a critical element in tumor growth. Live animal imaging demonstrated that AnxA2-PNPs and AnxA2-CPNPs effectively targeted and accumulated in the tumor as seen by the increased fluorescence intensity on the live scans. Xenograft studies in mice showed significant regression of breast tumor as a result of both effective targeting, accumulation and sustained release of curcumin in the tumor. In conclusion, AnxA2-CPNPs were successfully validated for their breast tumor targeting potential and its improved therapeutic efficacy against metastatic breast cancer.