Colorectal cancer (CRC), the most common malignancy of the gastrointestinal tract, is the second leading cause of cancer-related deaths worldwide. In this context, investigating low-penetrance gene variants associated with the increased risk of CRC represents a novel and crucial approach to enhancing prevention strategies and clinical surveillance. By focusing on these genetic variants, there is potential for more accurate prediction of individual CRC risk, which could contribute to the refinement of current screening and prophylactic programs. The aim of this case-control study was to explore the association between SIRT1 polymorphisms and CRC risk. We analyzed three SNPs-rs12778366 (T/C), rs3758391 (C/T), and rs7895833 (A/G)-in the promoter region of the SIRT1 gene, which may influence SIRT1 expression and thus play a role in cancer development. Our study included 200 patients with colorectal adenocarcinoma and 115 controls. Genomic DNA was extracted from blood samples, and SIRT1 SNP analysis was performed using the qPCR method and endpoint genotyping. Univariate regression analysis revealed a slightly increased risk of developing CRC in individuals with minor alleles of the analyzed polymorphisms; however, the observed differences were not statistically significant. Although our findings did not reveal statistically significant differences in SIRT1 gene polymorphism frequencies between the CRC group and the control group, we observed a tendency that suggests further investigation in larger cohorts is warranted. This research underscores the importance of understanding low-penetrance genetic factors in CRC, highlighting their potential to inform more personalized and effective prevention strategies.