Background: Colorectal cancer (CRC) ranks as the second most common gastrointestinal malignancy globally, surpassed only by stomach cancer in incidence. Colorectal cancer (CRC) is recognized as the second most prevalent gastrointestinal cancer worldwide, with stomach cancer being the only cancer that surpasses it in terms of incidence. Purpose: This research aims to examine the possible anti-carcinogenic effects of Urolithins A, B, C, and D, which are metabolites present in pomegranate juice. These metabolites will be compared to established drugs such as folinic acid, doxorubicin, and 5-fluorouracil (5-FU), often used in treating CRC. Method: In this study, we investigated the interactions between the epidermal growth factor receptor (EGFR) and three proteins, namely human epidermal growth factor receptor HER3 (Protein Data Bank (PDB) code: 3LMG), HER2 (PDB code: 3PP0), and HER1 (PDB code: 4AG8), utilizing the Protein Data Bank (PDB) principles. The findings of our study demonstrate the presence of persistent and reliable interactions within the protein-ligand complexes, specifically in the cases of 3PP0, 3LMG, and 4AG8, as indicated by the root mean square deviation (RMSD) values. Results: The 3PP0 complex demonstrated RMSD values spanning from 1.17 to 3.23 Å. The 3LMG complex exhibited root RMSD values ranging from 1.16 to 2.93 Å, with a standard deviation of 0.25. Similarly, the 4AG8 complex showed root mean square deviation of RMSD values ranging from 1.27 to 3.35 Å, accompanied by a standard deviation of 0.42. The root mean square fluctuations (RMSFs) observed in these complexes exhibited a range spanning from 0.42 to 7.65 Å, providing more evidence of the stability of the interactions. The endurance of Urolithin A (Uro A) was established through an investigation using density functional theory (DFT), yielding an E value of 4.2700 eV, energy of the highest occupied molecular orbital (E_HOMO) of –5.8560 eV, and energy of the lowest unoccupied molecular orbital (E_LUMO) of –1.5860 eV. Uro As in vitro anticancer potential has been evaluated through human colon adenocarcinoma cell line (HT-29) cell lines. The results of anticancer potential revealed that Uro A exhibited an half maximal inhibitory concentration (IC₅₀) value of 120.4087 ± 1.113, whereas doxorubicin showed a slightly lower IC₅₀ = 117.89 ± 0.537. Uro A has demonstrated promising therapeutic effectiveness by engaging many pathways, such as inducing apoptosis, increasing the expression of pro-apoptotic genes (p53 and p21), inhibiting B-cell lymphoma 2 (Bcl-2), activating caspase and inhibiting protein kinase B (AKT) 1 and 2, and reducing levels of reactive oxygen species (ROS) in CRC cells. Our study in the field of network pharmacology has revealed encouraging possibilities for the treatment of CRC. This study offers a complete analysis of the mechanisms contributing to the possible anti-CRC effects of urolithin polyphenol complexes. Absorption, Distribution, Metabolism, Elimination, and Toxicity (ADMET) analysis reveals the promising potential of Uro A required for future drug development. Conclusions: Our findings offer valuable insights for future CRC research and therapeutic strategy development, particularly in inhibiting AKT 1 and 2 and activating caspases to promote apoptosis, thereby contributing to effective CRC management.