Despite tremendous scientific efforts aimed at glioblastoma’s (GB) ability to escape therapeutic attempts, the concern remains unsolved. Postbiotics, metabolites, and macromolecules of probiotic bacteria could become adjuvant therapeutics both dealing with cellular events constituting tumor therapy escape mechanisms and protecting normal cells from therapy-induced damage. The study aims to evaluate the dual potential of postbiotics obtained from lactic acid bacteria, L. plantarum and L. rhamnosus, on patient-derived and commercially available GB and normal cells alone and in combination with chemotherapeutic and irradiation oncotreatment regimens. Postbiotic mixtures (PMs) show cytoprotective potential against a new anti-cancer agent—ARA12—on astrocytes and cytoprotective action to irradiated normal fibroblast cells. Although GB cells’ apoptotic response varied between patient-derived cells, both PMs exert cytotoxic or cytostatic effects alone and, in most of the studied therapeutic combinations, on all tested GB cell lines. In particular, L. plantarum PM alleviates treatment escape, possibly shifting the tumor drug response from senescence to apoptosis. The results suggest that postbiotic-based adjunctive treatment could potentiate the therapeutic effect toward neoplastic cells, while alleviating chemotherapy’s adverse effects, helping clinicians to tackle the issue of therapy resistance and improve patients’ comfort.