Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with high resistance and recurrence rate. Here we present a novel combination therapy composed of Selinexor, a selective nuclear export (XPO1) inhibitor, and 5-aminolevulinic acid (5-ALA), a protoporphyrin IX (PpIX) precursor. Selected drugs act through two distinct mechanisms of action: Selinexor retains tumor suppressor proteins within the nucleus, while 5-ALA, after being converted to PpIX, induces oxidative stress upon light exposure. Intracellular accumulation of PpIX in U-87 MG cells peaked at 4 h and co-administration of the drugs to U-87 MG cells yielded strong synergism with substantially reduced doses of 5-ALA and Selinexor up to ∼140- and ∼ 29-fold, respectively. Conversely, very strong antagonism was observed in the control cell line. While the highest mitochondrial H₂O₂ production was measured following 5-ALA induced photodynamic therapy (PDT), Selinexor reduced H₂O₂ level. The strong synergistic interaction between the two drugs enhanced therapeutic outcome by suppressing cell migration and inducing apoptosis with markedly lower drug doses. These findings suggest that the combination therapy of Selinexor and 5-ALA/PDT may increase the chances of successful GBM treatment compared to monotherapy alone.