Trastuzumab and Tamoxifen are two of the most often recommended anti-cancer drugs for breast cancer (BC). To date, anticancer drugs' impacts on BC's proteome and metabolic pathways have been studied in only a few studies. Integrating promising metabolomics and proteomics as an emerging technology will enable investigators to discover new biomarkers for monitoring drug response and potential therapeutic targets. We explored the effect of the anticancer drugs Tamoxifen 5 μM and Trastuzumab 2.5 μM, both separately and in combination, on metabolomic profile of MCF-7 and SkBr3 breast cancer cells followed by proteomic and metabolic profile of BT-474 breast cancer cells. To investigate changes in treated breast cancer cells, we utilized ultra-high-performance liquid chromatography-quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS). A total of 98 metabolites were found to significantly differ in abundance in MCF-7 and SkBr3 treated cells, while total of 77 proteins and 85 metabolites were found to significantly differ in abundance in BT-474 treated cells compared to controls. Based on the metabolomic based analysis of MCF-7 and SkBr3 cells, our results demonstrated that the treatments with Tamoxifen and/or Trastuzumab significantly affected energy production pathways such as fatty acid metabolism, glycerol metabolism, cancer cell symbiosis and glutamine theory, amino acid metabolism, the urea cycle, ammonia recycling, glycolysis, and gluconeogenesis, are crucial for the regulation of energy production and have been associated with the initiation, progression, and aggressiveness of cancer. As cancer cells depend on amino acids to fuel their growth through protein anabolism, it is also known that the metabolism of amino acids in cancer cells is disrupted. Amino acids are necessary for cellular redox homoeostasis and nucleoside synthesis, both of which are known to be disrupted in cancer, in addition to their potential role in energy production. On the other hand, multi-Omics based analysis of BT-474