CREB binding protein (CBP) is an acetyltransferase that plays an important role in many biological processes. Here, we show that Akt phosphorylates CBP at threonine 1871 and suppresses its acetyltransferase activity by impeding the binding of CBP to histone H3, which results in a decrease in lysine K18 acetylation and dysregulation of target genes. Our results demonstrate that Akt regulates acetyltransferase activity through CBP phosphorylation, which may contribute to tumorigenesis.