Casein kinase 1⍺ (CK1⍺) is a multifunctional serine/threonine kinase, serving as an upstream regulator of the p53 pathway and a potential therapeutic target for acute myeloid leukemia (AML). Small-molecule degraders show preclinical promise in AML by selectively degrading target proteins. Here, we developed and evaluated PinA1, a molecular glue degrader targeting CK1⍺, in preclinical AML models. PinA1 preferentially degraded CK1⍺ at nanomolar concentrations, resulting in enhanced p53 expression, cell-cycle arrest, and apoptosis in TP53 wild-type AML cell lines but not in TP53 mutated cells. PinA1 also induced CK1⍺ degradation and p53-dependent apoptosis in primary AML cells with wild-type TP53. Notably, PinA1 had minimal effects on the viability of human peripheral blood and bone marrow mononuclear cells, including CD34+ cells, with limited activation of the p53 pathway. In both cell lines and primary AML cells, PinA1 enhanced apoptosis when combined with targeted agents, including FLT3, BCL-2, or MDM2 inhibitors. PinA1 demonstrated robust anti-leukemic efficacy as a monotherapy and exhibited synergistic effects when combined with targeted agents in xenografts derived from human AML cell lines and primary AML cells. In conclusion, PinA1 degrades CK1⍺, activates the p53 pathway, and induces cell-cycle arrest and apoptosis in TP53 wild-type AML cells. The robust anti-leukemic efficacy of PinA1, both as monotherapy and further in combination with targeted agents, along with its minimal toxicity to normal hematopoietic cells, underscores its potential for future clinical applications.