Given the importance of cyclin-dependent kinases (CDKs) in the maintenance of cell development, gene transcription, and other essential biological operations, CDK blockers have been generated to manage a variety of disorders resulting from CDK irregularities. Furthermore, CDK9 has a crucial role in transcription by regulating short-lived anti-apoptotic genes necessary for cancer cell persistence. Addressing CDK9 with blockers has consequently emerged as a promising treatment for cancer. This study scrutinizes the effectiveness of nature-derived compounds (geniposidic acid, quercetin, geniposide, curcumin, and withanolide C) against CDK9 through computational approaches. A molecular docking study was performed after preparing the protein and the ligands. The selected blockers of the CDK9 exerted reliable binding affinities (−8.114 kcal/mol to −13.908 kcal/mol) against the selected protein, resulting in promising candidates compared to the co-crystallized ligand (LCI). The binding affinity of geniposidic acid (−13.908 kcal/mol) to CDK9 is higher than quercetin (−10.775 kcal/mol), geniposide (−9.969 kcal/mol), curcumin (−9.898 kcal/mol), withanolide C (−8.114 kcal/mol), and the co-crystallized ligand LCI (−11.425 kcal/mol). Therefore, geniposidic acid is a promising inhibitor of CDK9. Moreover, the molecular dynamics studies assessed the structure–function relationships and protein–ligand interactions. The network pharmacology study for the selected ligands demonstrated the auspicious compound–target–pathway signaling pathways vital in developing tumor, tumor cell growth, differentiation, and promoting tumor cell progression. Moreover, this study concluded by analyzing the computational approaches the natural-derived compounds that have potential interacting activities against CDK9 and, therefore, can be considered promising candidates for CKD9-induced cancer. To substantiate this study’s outcomes, in vivo research is recommended.