Our study demonstrates that SOX9 dramatically activated the PI3K/Akt signaling pathway, followed by the upregulation of p-Akt, cyclin D1, p-FOXO1, and p-FOXO3, and the downregulation of p21Cip1 and p27Kip1, resulting in the promotion of ESCC proliferation and tumorigenicity. Here, CDKN1B is linked to esophageal squamous cell carcinoma.