Breast cancer is the most common cancer in women. Triple Negative Breast Cancer (TNBC) is the greatest invasive class, with poor prognosis due to side effects exerted by chemotherapy and the low effectiveness of novel treatments. In this sense, copper compounds have shown to be potentially effective as antitumor agents, attracting increasing interest as alternatives to usually employed platinum-derived drugs. The aim of this work is to evaluate the antitumoral activity of a series of copper (II) compounds in 2D and 3D cancer models: two monomeric complexes derived from thiophene hydrazide (1) and methoxyphenyl hydrazide (2), and a dimeric complex derived from furane hydrazide (3). The cytotoxic activity in the 2D model was tested against two breast cancer cell lines MDA-MB-231 (TNBC) and MCF7. The complexes significantly reduced cell viability in both cell lines (MDA-MB-231 IC50: 1 1.65µM, 2 1.56µM, 3 1.30µM; MCF7 1 1.67µM, 2 1.70µM). Antitumoral activity of 1 and 2 was tested in MCF7 3D models. Complexes diminished cell viability of spheroids (IC50: 1 2.64µM; 2 2.23µM), affecting the spherical shape. Moreover, pretreatment of cells with 1 and 2 lead to a decrease in mammosphere formation. Further analysis demonstrated that the complexes conveyed cells to apoptosis and decreased cancer stem cell population. Moreover, 1 and 2 showed a great genotoxicity, and inhibition of proteasomal activity. Finally, label-free quantitative proteomics was used to identify the molecular mechanisms of 1 and 2 in TNBC cells. Both complexes increased proteins involved in ER stress and UPR, as well as down-regulated proteins related to DNA replication and repair, in addition to GOF-mutant p53. Moreover, we found a novel and interesting effect for a copper metallodrug, the down-regulation of proteins related to lipid synthesis and metabolism. Taken together, these results suggest that these complexes are good potential candidates to evaluate on breast in vivo assays.