Colorectal cancer (CRC) constitutes a major global health concern, ranking as the third most common cancer and the second leading cause of cancer-related mortality. The current review explores sex-based differences in CRC epidemiology, risk factors, tumor biology, and clinical outcomes. Males exhibit a higher incidence and mortality rate, with left-sided (distal) CRC predominating, while females are more frequently diagnosed with right-sided (proximal) tumors, which tend to be more aggressive and less responsive to conventional chemotherapy. Genetic disparities, including microsatellite instability and X-chromosome tumor suppressor genes, contribute to sex-specific differences in tumor progression and treatment response. Immune variations also influence disease outcomes, with females exhibiting stronger immune surveillance but higher exhaustion markers. Lifestyle factors such as body mass index (BMI), smoking, and hormonal influences further modulate CRC risk. While males are more vulnerable to obesity-related CRC, central obesity (waist-to-hip ratio) emerges as a stronger predictor in females. Additionally, smoking increases CRC risk differentially by tumor location. These findings underscore the importance of sex-specific approaches in CRC prevention, screening, and treatment, advocating for personalized medicine strategies tailored to gender-based biological and clinical distinctions.