This study identifies a critical dependency of POU2F3-driven small cell lung cancer (SCLC-P) and POU2AF1-dependent multiple myeloma (MM) on the mSWI/SNF chromatin remodeling complex. The mSWI/SNF complex, particularly its ATPase subunit, is essential for the function of these transcription factors, which drive oncogenic signaling. Targeting the mSWI/SNF complex with a proteolysis targeting chimera (PROTAC) degrader, AU-24118, effectively evicts POU2F3 and its coactivators from chromatin, leading to reduced downstream signaling and tumor growth inhibition in preclinical models of SCLC-P and MM. The degrader shows potent antitumor efficacy without significant toxicity, suggesting that targeting the mSWI/SNF complex represents a promising therapeutic strategy for these cancers. The study also highlights the potential of mSWI/SNF ATPase degraders in other POU2F/POU2AF-driven malignancies, emphasizing the importance of targeting transcription factor coactivators in cancer therapy.This study identifies a critical dependency of POU2F3-driven small cell lung cancer (SCLC-P) and POU2AF1-dependent multiple myeloma (MM) on the mSWI/SNF chromatin remodeling complex. The mSWI/SNF complex, particularly its ATPase subunit, is essential for the function of these transcription factors, which drive oncogenic signaling. Targeting the mSWI/SNF complex with a proteolysis targeting chimera (PROTAC) degrader, AU-24118, effectively evicts POU2F3 and its coactivators from chromatin, leading to reduced downstream signaling and tumor growth inhibition in preclinical models of SCLC-P and MM. The degrader shows potent antitumor efficacy without significant toxicity, suggesting that targeting the mSWI/SNF complex represents a promising therapeutic strategy for these cancers. The study also highlights the potential of mSWI/SNF ATPase degraders in other POU2F/POU2AF-driven malignancies, emphasizing the importance of targeting transcription factor coactivators in cancer therapy.