Background: Colon cancer is one of the most prevalent cancers in the world; some of its risk factors are controllable. A healthy lifestyle and early diagnosis significantly reduce colon cancer incidence and mortality. The aim of this study was to assess the most important risk factors for colon cancer in the Egyptian patients as well as the usefulness of miRNA-122 as diagnostic biomarker for colon cancer. Methods: In this case control study, 102 colon cancer cases and equal number of controls were enrolled between April 2022 till June 2022 in two Egyptian centers. Both groups were assessed by a structured questionnaire, anthropometric measurements and serum levels of miRNA-122. Results: Dietary factors, older age, obesity, rural residence, prolonged use of non-steroidal anti-inflammatory drugs, and cigarette smoking were significantly associated with colon cancer in our study subjects. miRNA-122 demonstrated significant sensitivity and specificity for colon cancer diagnosis, with a cutoff value of 0.946. Conclusion: The most important risk factor for colon cancer in the Egyptian patients were smoking, obesity, diabetes, dyslipidemia and excessive processed meat intake with low vegetables consuption. Our study suggests miRNA-122 as a potential non-invasive diagnostic biomarker for colon cancer.