Background: Herbal medicines, particularly those rich in polyphenolic compounds, have been proposed to be chemotherapeutic factors, which can modulate several pathways associated with cancer. To gain mechanistic insights into the anti-proliferative impacts of Cornus mas extract (CME), this study investigated the expression changes of several prominent genes, which involved in malignancy with therapeutic potential. Objectives: The aim of the study was to determine the anticancer potential of CME on the main regulatory genes in renal carcinogenesis. Methods: To perform the research, Caki-1 cancer cells were incubated for 72 h with 250 mu g/ml of CME upon the cells with ribonucleic acids (RNAs) extracted for identified alterations of human telomerase reverse transcriptase (hTERT), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (Her2), and B-cell lymphoma-2 (Bcl-2) gene expressions by a quantitative reverse transcription-polymerase chain reaction. The changes in protein expression were analyzed by the western blot method. Cell apoptosis was detected using the flow cytometry technique. Results: Cornus mas extract caused down-regulated Bcl-2 as an anti-apoptotic 4.34-fold gene expression. Moreover, Her2 oncogene messenger RNA expression was inhibited by 250 mu g/ml concentration of similar to 10-fold CME. The antitumor activity of CME was pronounced in its potent anti-angiogenic potential, as CME resulted in a striking decrease in similar to 125-fold expression of VEGF compared to the untreated control. In contrast, CME led to similar to 2.6-fold up-regulation of hTERT in Caki-1 cancer cells. Conclusion: Overall, various molecular pathways were formed to interplay with Caki-1 cells, which depended on the active phenolic compound of CME. It is recommended to perform further studies to investigate the effect of unique polyphenols of the total extract of CME to establish an effective strategy for renal cancer treatment.