Glioblastoma (GBM), the most aggressive of primary brain tumors, determine short survival and poor quality of life. Therapies used for its treatment are not effective and chemotherapy failure is partially due to multidrug resistance (MDR) mechanisms present in the tumor cells. New therapeutic strategies are needed in order to improve survival in GBM. The present study investigated the activity of the pentacyclic triterpene pomolic acid (PA) in GBM. Pomolic acid decreased the viability and induced apoptosis of GBM cells as demonstrated by DNA fragmentation. It also induced uncoupling of mitochondria membrane potential and activation of caspase-3 and -9. Pomolic acid-induced apoptosis is dependent on reactive oxygen species (ROS) production as it is inhibited by anti-oxidant treatment. Pomolic acid also down-modulated the activity of the multidrug resistance associated protein 1 (MRP1) and inhibited migration of GBM cells. These results show that PA acts on several pathways of GBM drug resistance and therefore may be of potential interest for the treatment of this tumor.