The NPM-ALK fusion constitutively activates ALK tyrosine kinase, driving oncogenesis in anaplastic large cell lymphoma (ALCL). Although arsenic trioxide (ATO) exhibits therapeutic potential in NPM-ALK⁺ ALCL by inhibiting proliferation and inducing apoptosis, its molecular mechanism remains unclear. Here, we used a combined approach of E3 ligase library screening, ATO chemical proteomics, and NPM-ALK immunoprecipitation–mass spectrometry to reveal that ATO regulates NPM–ALK stability via the E3 ligase STUB1. Comprehensive clinical data indicate that high STUB1 expression correlates with improved prognosis in NPM-ALK⁺ ALCL patients. In ALCL cells, both ATO treatment and STUB1 overexpression induce NPM-ALK degradation and suppress cell growth. Mechanistically, ATO functions as a molecular glue that stabilizes the ternary complex of STUB1 and NPM-ALK, promoting ubiquitination at K174 and subsequent proteasomal degradation. Furthermore, structural modeling identified C83 as an arsenic-bound site in STUB1 that modulates the STUB1-NPM-ALK interface, thereby enhancing their interaction and promoting ubiquitin-mediated degradation. Moreover, STUB1 overexpression or activation by Lanatoside C or Deslanoside markedly inhibits NPM‑ALK⁺ ALCL cells proliferation and synergizes with ATO in vitro and in vivo. These findings provide novel mechanistic insight into ATO’s action in NPM‑ALK⁺ ALCL and reveal new therapeutic strategies and clinical biomarkers for patient management.