Significance Merkel cell carcinoma (MCC) is an aggressive skin cancer. While virus-negative [Merkel cell polyomavirus (MCV)] MCC contains inactivating mutations in RB and p53, MCV-positive MCC usually contains wild-type RB and p53. We demonstrate that MCV large T antigen binding to RB results in p53 activation, while MCV small T antigen reduces p53 activation by increasing levels of MDM2 and CK1 α , an activator of MDM4. Targeted degradation of CK1 α by lenalidomide or a specific MDM4 inhibitor acts synergistically with MDM2 inhibitors to activate p53 and induce apoptosis. Our work uncovers the mechanism behind MCV control of p53 in MCC and demonstrates the utility of targeting MDM2 and MDM4 combinatorially in p53 wild-type tumors.