Abstract: Objective To investigate the associations of multiple glycolipid metabolic indicators and their cumulative abnormality burden with incident colorectal cancer risk in a general population-based prospective cohort, and to examine the mediating role of glycolipid metabolic abnormalities in the relationships between smoking, alcohol consumption, physical activity, and colorectal cancer incidence. Methods A total of 17 897 eligible participants recruited from the Taizhou cohort from 2011 and 2014 were included. Cox proportional hazards regression models were used to assess the associations of conventional and derived glycolipid indicators, as well as a glycolipid abnormality index constructed from total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting plasma glucose, and insulin, with incident colorectal cancer risk. Restricted cubic spline models were applied to evaluate dose-response relationships for major indicators. Receiver operating characteristic curves were generated to compare predictive performance across indicators. Mediation analyses were conducted to assess the mediating effects of the glycolipid abnormality index on the associations between smoking, alcohol consumption, physical activity, and colorectal cancer incidence. Results During a median follow-up of 11.2 years, 102 incident colorectal cancer cases were identified, with an incidence density of 51.2 per 100 000 person-years. After adjustment for potential confounders, Cox proportional hazards regression analyses showed that decreased high-density lipoprotein cholesterol was associated with a 1.74-fold higher risk of colorectal cancer (HR=1.74, 95%CI: 1.03-2.95), elevated low-density lipoprotein cholesterol was associated with a 1.78-fold higher risk (HR=1.78, 95%CI: 1.05-3.02), and abnormal fasting plasma glucose was associated with a 1.86-fold higher risk (HR=1.86, 95%CI: 1.15-3.02). Fasting plasma glucose showed an approximately linear increasing association with colorectal cancer risk. The glycolipid abnormality index showed a clear gradient association with colorectal cancer risk; participants with three or more abnormal indicators had a 3.08-fold higher risk than those without abnormalities (HR=3.08, 95%CI: 1.60-5.92). The area under the curve was 0.795, higher than that of individual glycolipid indicators and other combined indices, and sex-stratified analyses showed generally consistent patterns. Glycolipid metabolic abnormalities partially mediated the associations of smoking, alcohol consumption, and physical activity with colorectal cancer incidence, with mediation proportions of 8.33%, 9.45%, and 9.04%, respectively. Conclusion Glycolipid metabolic abnormalities were associated with an increased risk of colorectal cancer incident. The glycolipid abnormality index showed an increasing relationship with colorectal cancer risk and demonstrated better discrimination, and it partially mediated the associations between smoking, alcohol consumption, physical activity, and colorectal cancer incidence in the overall population.