Glioblastoma (GBM) is one of the most treatment-resistant brain malignancies. Dysregulation of Wnt/β-catenin signaling might be implicated in tumorigenesis of GBM. In this study, spatial transcriptomic analysis revealed elevated expression of Wnt target genes within tumor regions compared with peritumoral tissues. Overexpression of porcupine (PORCN), an O-acyltransferase for Wnt secretion, correlated with poor prognosis of GBM patients. Treatment with Wnt-C59, a PORCN inhibitor, inhibited Wnt signaling, hindered GBM cell proliferation and invasion, and inhibited GBM stem cells' self-renewal properties in a dose-dependent manner. Moreover, using β-catenin knockout and knockdown cells, FOXM1 was identified as a downstream transcription target of Wnt/β-catenin signaling. Wnt-C59 inhibited the expression of FOXM1 in GBM cells. Furthermore, Wnt-C59 demonstrated the ability to impede tumor formation and enhance the overall survival of mice bearing GBM in a preclinical model. Notably, the combined treatment of Wnt-C59 with temozolomide further enhanced therapeutic outcomes, leading to a significant extension of overall survival in GBM-bearing mice. Mechanistically, Wnt-C59 significantly down-regulated the expression of oncogenic targets associated with Wnt/β-catenin signaling (FOXM1, cyclin D, and C-Myc) both in vitro and in orthotopic GBM models. Our findings reveal that targeting Wnt/β-catenin signaling via PORCN inhibition, especially in combination with temozolomide, offers a promising therapeutic strategy for treating GBM.