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Despite the central role of p53 suppression in cancer pathogenesis, the promise of therapeutic p53 reactivation remains unrealized, with targeted and combination chemotherapies limited by efficacy, toxicity, and delivery. To overcome these challenges, we introduce a triple-action proteolysis targeting chimera (TAPTAC) that simultaneously targets three oncogenic mechanisms to reactivate apoptosis. TAPTAC1 diverts HDM2 from degrading p53 to eliminating oncogenic targets such as BET proteins, while also blocking HDMX-mediated sequestration, thereby maximizing p53 reactivation in concert with cancer protein degradation. TAPTAC1 outperforms combination treatments and PROTACs that target HDM2 and BET proteins, but not HDMX, and is broadly effective in wild-type (WT) p53 cancers, including mouse models of osteosarcoma and leukemia. Importantly, TAPTAC1 leverages cancer dependency on HDM2 to enhance selectivity and mitigate toxicity. With WT p53 retained in 90% of pediatric and 50% of adult cancers, TAPTACs provide a therapeutic platform for addressing key limitations of prior anti-cancer strategies.