(1) Background: Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer deaths worldwide. It often diagnosed at advanced stages, and with increasing incidence at younger generation. CRC poses a heavy financial burden and a huge public health challenge nowadays. Lipoproteins and serum lipids may have an influence on carcinogenesis by making oxidative stress, inflammation, and insulin resistance. Dyslipidemia plays a potential role in the risk of CRC. The purpose of this study is to use nationally representative samples to determine epidemiologic characteristics of CRC in the Taiwanese population, and to evaluate the associations between baseline levels of lipid profile and their effect on risk of colorectal cancer (CRC) comprehensively and quantitatively. The control of dyslipidemia in primary and secondary prevention may reduce the disease burden of CRC. (2) Methods: This is a nationwide long-term community-based prospective cohort study. Data were retrieved from the nationwide population-based Taiwanese Survey on Hypertension, Hyperglycemia and Hyperlipidemia (TwSHHH). Variables were estimated by the Cox proportional hazards model which was then further adjusted for age. We also calculated the relative ratios (RRs) of CRC for joint categories of serum cholesterol, triglyceride (TG), low-density lipoproteins cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) level, and to examine their combined effect and statistical interactions. (3) Results: Male, age, waist circumference, diabetes mellitus (DM), high TG, high cholesterol level, smoking history, and metabolic syndrome were proved to increase the risk of CRC. In addition, DM patients with a TG level ≥150 mg/dL and cholesterol ≥180 mg/dL had a 4.118-fold higher risk of CRC as compared with a TG level <150 mg/dL and cholesterol level <180 mg/dL, which was a significant difference (95% CI, 1.061–15.975; p = 0.0407). (4) Conclusions: Patients with DM should control TG and cholesterol level through diet, exercise, or taking medications more aggressively, not only for preventing cardiovascular disease, but also for first prevention of CRC. The study can be valuable for the clinicians and policy makers to implement more precisely goals about dyslipidemia management.