CD44 receptor and mitochondria targeting hyaluronic acid-D-a-tocopherol succinate-(4-carboxybutyl)triphenyl phosphonium bromide (HA-TS-TPP)-based nanoparticles (NPs) were designed for the delivery of lapatinib (LPT) to triple-negative breast cancer (TNBC). While LPT is one of the dual tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR) and human EGFR2 (HER2), TNBC cells often exhibit EGFR positive and HER2 negative patterns. Along with the HER2-independent anticancer activities of LPT in TNBC, apoptosis-inducing properties of TPP and TS (resulting from mitochondrial targeting and destabilization) were introduced to amplify the anticancer activities of HA-TS-TPP/LPT NPs for TNBC. HA-TS-TPP/LPT NPs, with approximately 207 nm mean diameter, unimodal size distribution, spherical shape, negative zeta potential, and sufficient particle stability, were prepared in this study. The improved antiproliferation potential, apoptotic efficacy, and mitochondria] destabilizing activity of HA-TS-TPP/LPT NPs, compared with HA-TS/LPT NPs, were demonstrated in TNBC (i.e., MDA-MB-231) cells. The in vivo tumor targeting capability of HA-TS-TPP/LPT NPs was proven in MDA-MB-231 tumor-bearing mouse models using real-time optical imaging. Of note, HA-TS-TPP/LPT NPs exhibited a better tumor growth suppression profile than the other groups after intravenous injection. It is expected that developed HA-TS-TPP NPs can elevate the therapeutic potential of LPT for TNBC.