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Approximately 96% of myelofibrosis (MF) patients express wild-type (WT) p53. MF hematopoietic stem/progenitor cells (HSPCs) overexpress MDM2 that degrades WTp53, thereby supporting MF HSPC survival. Although MDM2 small-molecule inhibitors (SMIs) are clinically effective, their benefit is compromised by an inability to sufficiently deplete MF HSPCs. KT-253 degrades MDM2 and overcomes the p53-dependent feedback loop that restores MDM2 levels observed with the use of MDM2 SMIs such as AMG-232. We evaluated the effects of KT-253 using MPN cell lines, primary MF CD34⁺ cells, and a mouse xenograft model. KT-253 activity was correlated with activation of the p53 pathway and upregulation of p53 downstream genes, including p21, NOXA, and PUMA in WTp53 UKE-1 cells but not p53 mutant cells. KT-253 treatment induced apoptosis of primary MF CD34⁺ cells at a tenfold lower concentration than AMG-232 and prevented the upregulation of MDM2 seen with AMG-232. Low doses of KT-253 reduced total MF colony and JAK2V617F⁺ colony numbers to a far greater extent than log-higher doses of AMG-232 (60% and 71% versus 20% and 10%, respectively). Mouse xenograft studies indicated that KT-253 more effectively depleted JAK2V617F⁺ MF marrow-repopulating cells. These findings support the further clinical evaluation of MDM2 degraders for the treatment of MF patients.