Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, contributing to the majority of breast cancer-related death. While chemotherapeutics (such as, paclitaxel) are the mainstay of systemic treatment for TNBC, they also enrich a subpopulation of cells with tumor-initiating capacity and stem-like characteristics called cancer stem cells (CSCs). CSCs are known to contribute to disease relapse; thus, research has focused on the development of an effective TNBC treatment through the inhibition of this subpopulation. Cancer nanomedicine, where nanoparticles are used to carry drugs to the tumor site, has revamped the field of cancer drug development, as it allows for a high therapeutic index and increases treatment efficacy. In this study, we developed a new therapy by co-encapsulating the clinically approved drugs; paclitaxel, verteporfin, and combretastatin (CA4) in polymer-lipid hybrid nanoparticles (NPs) made of FDA-approved biomaterials. Verteporfin is used in the treatment of macular degeneration but has recently also been shown to inhibit the Hippo/YAP (Yes-associated protein) pathway; known to be active in TNBC, contributing to its progression and CSC development. CA4 is a vascular disrupting agent targeting angiogenesis and has been tested in phase II/III clinical trials. Our results show that the new three drug-NP effectively inhibited TNBC cell viability, cell migration, and significantly reduced paclitaxel-induced and/or CA4-induced CSC enrichment. Furthermore, using a zebrafish in vivo model to visualize angiogenesis, we found that the combination of CA4 and verteporfin more effectively inhibited angiogenesis. Lastly, to further test the efficacy of the triple drug-NPs, we used a clinically relevant patient-derived xenograft (PDX) model. The triple drug-NP inhibited the viability of PDX slice cultures ex vivo and slowed down the growth of PDX tumors in an in vivo mice model. Our study therefore demonstrates an approach that is capable of simultaneously inhibiting bulk cancer cells, CSCs, and angiogenesis.