BTB domain and CNC homology 1 (BACH1) has been reported to be a vital regulator of tumor progression. However, methods for targeting BACH1 in cancers have not been fully researched. In this study, we identified BACH1 as a poor prognosis-related factor in patients with GBM. Furthermore, a small-molecule compound, HPPE, was found to interact with BACH1 and inhibit the progression of GBM in vitro and in vivo. Molecular dynamics analysis, molecular docking simulation, MST assay, and co-IP experiments revealed that HPPE principally binds to BACH1 at the bZIP domain on the C-terminus and promotes the competitive binding of BACH1 and TCF-4, thus inhibiting formation of the β-catenin/TCF-4 complex. HPPE incubation inhibited proliferation, promoted apoptosis, and induced G2/M arrest, indicating a potential synergistic effect with temozolomide in GBM cells. RNA-seq, qRT‒PCR, and gene enrichment analyses revealed that the induction of HPPE repressed the Wnt/β-catenin pathway. Further experiments revealed that BTB domain deletion from BACH1 eliminated its ability to interact with TCF-4 and significantly rescued the inhibition of Wnt/β-catenin signaling and the reduction of malignant phenotype induced by HPPE in GBM cells. In vivo experiments revealed that HPPE prolonged the survival time of mice, inhibited Wnt/β-catenin pathway activity and had a synergistic effect with TMZ in a xenograft model. In summary, these findings provide potential combined therapeutic strategies for glioma by targeting the C-terminus of BACH1 and inhibiting the activation of WNT signaling.