This study aimed to evaluate the inhibitory potential of Ginkgo biloba polyphenols against colorectal cancer biomarkers through in-silico analysis. The biomarkers investigated included KRAS-G12D, BRAF-V600E, PIK3CA-E545K, NRAS-Q61K, and DCC-T315I, which are commonly associated with colorectal cancer. In-silico docking simulations were conducted using the MOE software to assess the affinity of Ginkgo biloba polyphenols for the active sites of the mutant codons. A total of 152 ligands were docked, and their interactions and docking scores were analyzed. The results revealed significant inhibitory potential of Ginkgo biloba polyphenols against the mutant codons under investigation. Ligands such as quercetin-3-O-6''-rhamnosyl-2''-(6'''-p-coumaroylglucosyl)glucoside (L15), quercetin 3-O-[2-{6'-(7''''-O-glucosyl)-trans-p-coumaroyl)}-glucosyl]-rhamnoside (L17), and isorhamnetin-3-O-alpha-L-rhamnosyl-2''-(6'''-p-coumaroyl)-beta-D-glucoside (L47) demonstrated promising therapeutic potential. These ligands exhibited multi-targeting effects by interacting with multiple mutant codons simultaneously. L15 interacted with BRAF-V600E and PIK3CA-E545K, L17 targeted BRAF-V600E and DCC-T315I, and L47 showed affinity for both KRAS-G12D and PIK3CA-E545K. The findings suggest that Ginkgo biloba polyphenols, including L15, L17, and L47, have potential as therapeutic agents against colorectal cancer mutant codons. Their multi-targeting effects offer new opportunities for therapeutic development. Further investigations are needed to fully explore the therapeutic potential of these natural compounds and their application in cancer treatment. Overall, this in-silico study provides valuable insights into the inhibitory potential of Ginkgo biloba polyphenols against colorectal cancer biomarkers. The findings contribute to the field of natural compound-based cancer therapeutics and highlight the significance of multi-targeting approaches in developing effective treatments for complex diseases.