Despite the well-established link between human papillomavirus (HPV) and cervical and anogenital cancers, there is ongoing debate regarding the relationship between HPV and colorectal cancer (CRC). This study aimed to evaluate the causal connection between HPV infection and CRC. To achieve this, we conducted a Mendelian randomization analysis utilizing data from genomewide association studies (GWAS) to explore the association between HPV and CRC. Our analysis revealed a significant association between genetically predicted HPV-16 infection and the risk of paternal colorectal adenocarcinoma (HPV-16: OR 1.058, 95% CI 1.013 to1.102; p = 0.011), as well as CRC (HPV-16: OR 1.045 95% CI 1.005 to 1.085; p = 0.025). These findings provide compelling evidence for a causal effect of HPV-16 on the development of CRC. Further investigations into the underlying mechanisms and elucidation of this association are necessary to identify viable interventions for the prevention and treatment of HPV-16-associated CRC.