Glioblastoma multiforme (GBM) is the most common and highly aggressive form of brain cancer. The conventional standard of care treatment for GBM is surgical resection followed by radiotherapy combined with the chemotherapeutic alkylating agent Temozolomide (TMZ), that induces DNA damage and cell proliferation arrest as well as apoptotic cell death. However, many GBM tumours are intrinsically resistant to TMZ, making this malignant disease challenging to treat. The aim of this study was to evaluate the therapeutic potential of targeting pro-survival BCL-2 family proteins with BH3-mimetic drugs in human GBM cells in vitro as single agents or dual therapy when combined with TMZ, the bromodomain inhibitor JQ1 or small molecule inducers of ferroptosis. For in vitro evaluation, we used a panel of 6 human GBM cell lines and patient derived glioma neurospheres (PDNs), flow-cytometry based cell death assays and Western blotting. For in vivo studies, we used an orthotopic mouse model of GBM. We demonstrate that co-targeting the pro-survival proteins BCL-XL with ABT-1331852 and MCL-1 with S63845 was more potent at killing six GBM cell lines compared to conventional therapy with TMZ or JQ1.This correlated with abundant cleavage (activation) of caspase-3 and PARP1 protein detected by Western blotting. The combined loss of effectors of apoptosis, BAX and BAK, rendered U251 and SNB-19 cells refractory to any of the drug combinations tested demonstrating that apoptosis is responsible for their killing. In PDNs, the combination treatment of cells with S63845 and ABT-1331852, increased apoptotic cell death compared to single agent treatment of the BH3 mimetic drugs. In an orthotropic mouse model of GBM, we demonstrate that the BCL-XL inhibitor, A1331852 can penetrate the brain, with A1331852 detected in both tumour and healthy brain regions. We found that a BCL-XL plus an MCL-1 inhibitor potently cooperate with inducers of ferroptosis in killing U251 cells. Overall, these findings demonstrate the potential of dual targeting of distinct programmed cell death pathways in GBM and may guide the utility of BCL-XL inhibitors and inducers of ferroptosis with standard of care treatment for improved therapies for GBM.