Here, we unveiled a novel regulatory mechanism in ESCC in which TRIB2‐induced phosphorylation and activation of HDAC2 led to the deacetylation and transcriptional repression of p21, and the TRIB2/HDAC2 axis might be the dominant mechanism responsible for p21 suppression in ESCC, which ultimately mediates the effect of TRIB2 on CSC properties and radioresistance in ESCC. This evidence concerns the gene HDAC2 and esophageal squamous cell carcinoma.