CDK12 and CDK13 (CDK12/13) regulate transcription by phosphorylating Serine 2 (S2) of the C-terminal domain of RNA polymerase II and have been proposed as therapeutic targets in cancer. Here we report the development of CTX-439, a novel, orally bioavailable, ATP-competitive small-molecule CDK12/13 inhibitor. CTX-439 specifically inhibits S2 phosphorylation and downregulates many genes including those involved in DNA damage repair, thereby exerting a profound anti-cancer effect in vitro and in vivo including breast cancer PDX models. A CRISPR activation screen identified BCL-2 and BCL-xL, anti-apoptotic BCL-2 family members, as genes that when upregulated confer resistance to CTX-439. Simultaneous inhibition of BCL-2/BCL-xL and CDK12/13 rapidly induced apoptosis and significantly suppressed xenograft tumor growth. Mechanistically, CTX-439 downregulates MCL1 protein levels through transcriptional readthrough, shifting cell survival dependency to BCL-2 and BCL-xL. Our study provides novel insights into the anti-tumor effect of CDK12/13 inhibition and proposes a new combination therapy strategy with anti-apoptotic BCL-2 family inhibitors, which may improve therapeutic outcomes in cancer treatment.