Background: The risk of colorectal cancer (CRC) is known to increase in patients with metabolic disorders such as hypertension (HTN), hyperlipidemia (HLD), type 2 diabetes (T2DM), and metabolic associated fatty liver disease (MASLD). Both metabolic disorders and CRC share similar demographic, socioeconomic, geographic, and environmental risk factors. This study aims to examine the associations between metabolic syndrome-related diseases and CRC incidence, controlling for confounding risk factors. Methods: This was a propensity score matched case-control study using NIH All of UsResearch Program, Registered Tier version 7. CRC diagnoses was defined as having two or more diagnosis codes in EHR. We matched CRC patients to participants without CRC diagnosis with 1:2 ratio, aligning age, gender, race/ethnicity, income, education, region, and cigarette exposure. Income level per year ( < $25K, $25-100K, > $100K), education level (grade 12 or less, some college, college graduate), cigarettes exposure ( > 100 cigs per lifetime), region (Northeast, Midwest, South, West) were assessed using the survey. Height and weight measurement collected at the time of enrollment was used to calculate BMI and define obese (BMI ≥ 30 kg/m² ) and underweight (BMI < 18.5 kg/m²) status. We compared the average BMI between two groups, and calculated the odds ratios for obesity, underweight status, HTN, HLD, T2DM, and MASLD to assess the likelihood of these conditions being associated with colon cancer. Results: Between the control (n = 3,528) and CRC groups (n = 1,764), there was no significant differences in matched factors. The CRC group had a similar obesity prevalence and a lower mean BMI (28.8, SD 6.9) compared to the control group (29.3, SD 6.9, p = 0.017). Underweight status was linked to a 76% increase in CRC odds (OR 1.76, CI 1.21-2.56, p = 0.003), T2DM to a 26% increase (OR 1.26, CI 1.06-1.49, p = 0.008), HTN to a 58% increase (OR 1.58, CI 1.41-1.78, p < 0.001), HLD to a 32% increase (OR 1.32, CI 1.18-1.49, p < 0.001), and MASLD to over a two-fold increase (OR 2.16, CI 1.78-2.61 p < 0.001). Conclusions: Our study reinforces the significant link between metabolic dysregulation and CRC risk. The higher prevalence of metabolic disorders in the CRC group, despite a lower obesity prevalence and average BMI, suggests that other factors, potentially treatment effects, might contribute to these findings. Further research is warranted to elucidate the causal pathways linking metabolic disorders to the pathogenesis of CRC.