Inflammation is one of the major risk factors for cancer. Here, we show that calcium/calmodulin-dependent protein kinase II gamma (CAMK2γ) in intestinal epithelial cells (IECs) modulates inflammatory signals and promotes colitis-associated cancer (CAC) in mice. We have identified CAMK2γ as a downstream target of colitis-induced WNT5A signaling. Furthermore, we have shown that CAMK2γ protects against intestine tissue injury by increasing IEC survival and proliferation. Calcium/calmodulin-dependent protein kinase II gamma knockout mice displayed reduced CAC. Furthermore, we used bone marrow transplantation to reveal that CAMK2γ in IECs, but not immune cells, was crucial for its effect on CAC. Consistently, transgenic over-expression of CAMK2γ in IECs accelerated CAC development. Mechanistically, CAMK2γ in IECs enhanced epithelial signal transducer and activator of transcription 3 (STAT3) activation to promote survival and proliferation of colonic epithelial cells during CAC development. These results thus identify a new molecular mechanism mediated by CAMK2γ in IECs during CAC development, thereby providing a potential new therapeutic target for CAC.