Overexpression of CDKN1A—a downstream p53 gene—can trigger apoptosis in old cells but can also lead to chemoresistance and serve as a poor prognosis marker in cancer. This study explores apoptosis mechanisms via the p53 signaling pathway, focusing on the expression of CDKN1A (p21). Differential expression gene (DEG) analysis was performed on downstream p53 signaling genes using GSE23773 data from the Gene Expression Omnibus database, which includes whole human genome microarray data of colorectal cancer cells (HT-29) over time. Molecular docking simulations of compounds in ginger (Zingiber officinale Roscoe) ginger (Zingiber officinale Roscoe) against against TP53-related kinase (TP53RK), a protein that activates p53, were conducted to assess the potential of these compounds to influence downstream genes in the p53 signaling pathway. The DEGs were validated using machine learning and principal component analysis methods. Molecular docking and dynamic simulations of ginger compounds against TP53RK were performed on the crystal structure of the D-chain protein with PDB code 6WQX [D]. The docking scores of these compounds were then compared with pomalidomide, a known inhibitor of TP53RK. DEG analysis of GSE23773 data revealed that BAX, STEAP3 (TSAP6), AIFM2, SIVA1, GTSE1 (B99), and CDKN1A (p21) are downstream p53 genes whose expression undergoes regulatory changes in old HT-29 cells (day 7 cultures). Molecular docking and molecular dynamic simulation analysis indicated that gingerenone A, 6-shogaol, gingerol, and 6-paradol in Z. officinale Roscoe have the potential to down-regulate CDKN1A (p21) by inhibiting p53 activation through TP53RK and stable during 10ns. © 2024 the authors.