Glioblastoma (GB) is a primary malignancy of the central nervous system classified as a grade IV astrocytoma by the World Health Organization (WHO). Although GB rarely metastasizes, the prognosis is still poor. Moreover, the standard treatment for GB, temozolomide (TMZ), is liable to chemoresistance, which represents a major factor behind GB-related deaths. Investigating drugs with repurposing potential in the context of GB is worthwhile to bypass the lengthy bench-to-bedside research processes. The field of omics has garnered significant interest in scientific research due to its potential to delineate the intricate regulatory network behind tumor development. In particular, the utilization of proteomic and metabolomic analyses is a powerful approach for the investigation of metabolic enzymes and intermediate metabolites, data from which can further complement the field of systems biology since they represent the functional end of the cancer phenotype. Here, we have chosen two of the most widely prescribed anti-cancer drugs: cisplatin and paclitaxel. To our knowledge, current literature lacks studies examining their effect on the metabolic and proteomic alterations in GB. Our work employed the mass spectrometry technological platform 'UHPLC-Q-TOF-MS/MS' to examine the changes in the proteome and metabolome profiles of the U87 cell line with defined concentrations of cisplatin and/or paclitaxel, via an untargeted approach. Through this, a total of 1,419 distinct proteins and 90 metabolites was ultimately generated, for which subsequent analysis was performed. We observed that upon treatment with cisplatin (9.5 μM), U87 cells exhibited apparent efforts to cope with this exogenous stressor, understood the effect of paclitaxel (5.3 μM) on altering the transport machinery of the cell, and how the combination of cisplatin and/or paclitaxel suggests potential interactions with promising benefits in GB therapeutics. Thus, our research provides a detailed map of alterations in response to cispla