Glioblastoma multiforme, a highly aggressive and lethal brain tumor, is a substantial clinical challenge and a focus of increasing concern globally. Hematological toxicity and drug resistance of first-line drugs underscore the necessity for new anti-glioma drug development. Here, 43 anthracenyl skeleton compounds as p53 activator analogs were designed, synthesized, and evaluated for their cytotoxic effects. Five compounds (, , , , and ) exhibited good anti-glioma activity against U87 cells, with IC values lower than 2 μM. Notably, showed the best anti-glioma activity, with an IC value up to 0.53 μM, providing a promising lead compound for new anti-glioma drug development. Mechanistic analyses showed that suppressed the MDM4 protein expression, upregulated the p53 protein level, and induced cell cycle arrest at G2/M phase and apoptosis based on Western blot and flow cytometry assays.