<p>Breast cancer is a severe disease and every year its cases are increasing. In the present study, molecular docking analysis demonstrated that Pazopanib hydrochloride (PZH) interacts with key breast cancer targets, including HER-2, BCL2, PI3K and mTOR, highlighting its potential for repurposing as a therapeutic agent in breast cancer treatment. PZH is a BCS class II drug with low oral bioavailability (14–39%). To overcome these delivery challenges of PZH, lipid-polymer hybrid nanoparticles (PZH-P/L-NPs) were developed for treating triple-negative breast cancer. PZH-P/L-NPs showed nano-range particle size (129.76 ± 0.896&#xa0;nm) and uniform distribution (0.145 ± 0.024). The percentage EE was found to be 94.05 ± 0.05%. The nanoparticles showed good hemocompatibility and demonstrated a sustained release profile with 73.2% drug released within 48&#xa0;h. The in-vitro cell-based assays were performed to evaluate the efficacy of the developed PZH-P/L-NPs. The PZH-P/L-NPs showed high cytotoxicity in MDA-MB-231 cells with a 2.10-fold decrease in IC₅₀ value. The nanoparticles exhibited higher cellular uptake and substantial nuclear and morphological changes. PZH-P/L-NPs further exhibited increased ROS production, mitochondrial membrane potential disruption and apoptosis than free PZH. In an in-vitro 3D cell culture study, PZH-P/L-NPs demonstrated extensive loosening and dissociation of spheroids after 48&#xa0;h treatment than PZH, revealing their higher penetration ability. Moreover, higher cytotoxicity and apoptosis were also observed with PZH-P/L-NPs. Thus, developed PZH-P/L-NPs are promising strategy to enhance the efficiency of PZH for treating triple-negative breast cancer.</p> Graphical Abstract <p></p>