Although the inhibition of STAT3 phosphorylation and the downregulation of c-Myc and MMP9 are well-documented mechanisms targeted by numerous phytochemicals, our study highlights several aspects that contribute to its novelty and scientific significance: (1) Calanquinone A directly binds to STAT3, as supported by molecular docking analysis; (2) we utilized patient-derived primary GBM cells (Pt#3) to assess the functional effects of Calanquinone A; and (3) we employed an in vivo xenograft model to evaluate the therapeutic efficacy of Calanquinone A in glioblastoma. Here, STAT3 is linked to glioblastoma.