Talazoparib (TAL) has been effectively used for the treatment of gBRCA1/2-mutated HER2-negative metastatic breast cancer. However, acquired resistance to TAL remains a major challenge that impedes the clinical success of TAL treatment. Therefore, elucidation of proteins and pathways that contribute to or are affected by the TAL resistance is urgently needed to improve the treatment response and provide novel treatment strategies for advanced metastatic breast cancers. Herein, we aimed to investigate the altered protein signatures in TAL-resistant triple-negative breast cancer (TNBC) cells by comparing with the TNBC parental cell line via proteomic analysis. After validation of TAL-resistance by WST-1 and Annexin V analysis, two-dimensional gel electrophoresis (2DE)-based proteomic analysis coupled to matrix-assisted laser desorption/ionization (MALDI)-time of flight (TOF) mass spectrometry was performed to identify differentially regulated proteins. The findings revealed the identities of 10 differentially regulated proteins in TAL-resistant TNBC cells whose bioinformatic analysis predicted changes in EGF/FGF signaling pathways as well as in the AMPK signaling pathway. In addition, phosphorylation/dephosphorylation dynamics were predicted to be altered in TAL-resistant cells. The proteins identified in this study might be the targets to overcome TAL resistance for the treatment of TNBC.