Arsenic sulfide (AsS) is a mineral drug that can be administrated orally and has been applied in the treatment of myeloid leukemia. The aim of this work is to investigate the therapeutic effect of AsS in highly metastatic triple-negative breast cancer (TNBC) animal model, as AsS has not been applied in the treatment of breast cancer yet. To overcome the poor solubility of original AsS, a formulation of hydrophilic AsS nanoparticles (e-AsS) developed previously was applied to mouse breast cancer cells as well as the tumor-bearing mice. It was shown that e-AsS was much more cytotoxic than r-AsS, strongly inhibiting the proliferation of the cells and scavenging intracellular reactive oxygen species (ROS). The oral administration of e-AsS significantly increased the accumulation of arsenic in the tumor tissue and eliminated ROS in tumor tissues. Besides, e-AsS could also inhibit the activation of hypoxia-inducible factor-1α (HIF-1α) and NLRP3 inflammasomes. Consequently, the angiogenesis was reduced, the metastasis to lung and liver was inhibited and the survival of tumor-bearing mice was prolonged. In conclusion, e-AsS holds great potential for an alternative therapeutics in the treatment of breast cancer, due to its unique function of correcting the aggressive microenvironment.