Copper-based complexes have received attention due to promising antitumor activity both in vitro and in vivo. Drug delivery systems have been designed to address the drawbacks of anticancer drugs, including dose-limiting toxicity, chemoresistance, and poor water solubility. Eudragit® is a polymer widely utilized in pharmaceutical formulations to enhance the stability, solubility, and controlled release of drugs. Previously, we have synthesized and reported a novel copper(II)-hydrazone complex ([Cu(N-N-Fur)(NO3)H2O], CuHL1) that demonstrated an anticancer effect on triple-negative breast cancer (TNBC) cells. Next, our aim was to evaluate the combination of CuHL1 with Eudragit® on this type of cell. First, the nanoparticles containing Eudragit® E100 and S100 loaded with CuHL1 (ES-CuHL1) were synthesized by nanoprecipitation technique followed by ultrasonication. The formulation showed an encapsulation efficiency higher than 90%, with nanoparticles ranging from 253 nm (ES) to 342 nm (ES-CuHL1). By MTS assay we found that the nanoformulation induced significantly higher cytotoxicity on MDA-MB-231, 4T1, and HS578T TNBC cells compared to free compound at 0.75 µM (measured as cell viability respect to control cells; 4T1: 67±10% ES-CuHL1 vs. 94±4% CuHL1; HS578: 84±5% vs. 109±6%, p<0.05) and at 2 µM on MDA-MB-231: 41±6% vs. 60±3%). Moreover, the treatment with ES-CuHL1 increased the number of apoptotic cells compared to free compound, in every cell line. Finally, by clonogenic assays we observed a significant decrease in cell clonogenic capacity with nanoformulation compared to free CuHL1, at 0.5 µM in MDA-MB-231 and 4T1 cells (Clonogenic capacity respect to its control, 4T1: 72±7% ES-CuHL1 vs. 93±8% CuHL1; MDA-MB-231: 1±0% vs. 87±6% vs p<0.05). Overall, the findings suggest that ES-CuHL1 nanoparticles could be a more potent anti-tumor option compared to free CuHL1 against TNBC. Further research is required to evaluate its potential as a treatment for this type of tumor.