Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor in adults, characterized by rapid growth, diffusion, genetic heterogeneity, and resistance to existing therapies. Cilengitide, a cyclic peptide, has been known to inhibit angiogenesis and tumor growth in GBM by targeting integrins αvβ3 and αvβ5. In previous studies, cilengitide derivatives have shown antitumor effects in non-small cell lung cancer (NSCLC) by inhibiting epithelial-mesenchymal transition (EMT), migration, and invasion. Based on these results, this study investigated whether cilengitide and its derivatives inhibit cell migration and invasion of TMZ-resistant GBM cells by inhibiting the MAPK/Akt signaling pathway. In 2D and 3D cell culture experiments using T98G and U87MG cell lines, we confirmed that cilengitide and its derivatives effectively inhibited cell growth, migration, and invasion in TMZ-resistant glioblastoma (GBM) cells. Specifically, cilengitide derivatives induced apoptosis in TMZ-resistant glioblastoma cells and exhibited anti-migration and anti-invasion effects through inhibition of the MAPK/Akt signaling pathway. These inhibitory effects were further enhanced when combined with the multi-kinase inhibitor dovitinib. These results may provide valuable information for the development of peptide-based therapies for the treatment of TMZ-resistant glioblastoma (GBM) and potentially other cancers.