The signal transducer and activator of transcription 5 (STAT5) is an attractive therapeutic target but successful targeting of STAT5 has proved to be difficult. We report herein the development of AK-2292 as a first, potent and selective small-molecule degrader of both STAT5A and STAT5B isoforms. We designed a class of small molecules with micromolar binding affinity to STAT5 and similar or better binding affinity to STAT6, which are inactive in inhibition of STAT5 and STAT6 activity in cells. Using the PROTAC technology, we successfully transformed these functionally inactive STAT5/6 ligands into potent and selective STAT5 degraders exemplified by AK-2292. AK-2292 induces degradation of STAT5A/B proteins in a dose- and time-dependent manner and demonstrates an outstanding selectivity over all other STAT proteins and >6,000 non-STAT proteins, leading to selective inhibition of STAT5 activity in cells. RNA-seq analysis revealed that AK-2292 downregulates the transcriptome associated with STAT5A and STAT5B. AK-2292 displays potent cell growth inhibition in a panel of human chronic myeloid leukemia (CML) cell lines with activated STAT5. Of significance, AK-2292 effectively induces STAT5 depletion in normal mouse tissues and human CML xenograft tissues and achieves tumor regression in two CML xenograft mouse models at well-tolerated dose-schedules. Determination of co-crystals of AK-2292 and its corresponding STAT5 ligand in a complex with STAT5A provided their detailed interactions and a structural basis for further optimization. AK-2292 is not only a powerful research tool with which to investigate the biology of STAT5 and therapeutic potential of selective STAT5 protein depletion and inhibition in vitro and in vivo, but also a promising lead compound toward ultimate development of a STAT5-targeted therapy.