Background: Previous studies have examined the link between blood metabolic biomarkers and risk of thyroid cancer, with inconclusive results. We performed a cohort study based on the Swedish Apolipoprotein-Related Mortality Risk (AMORIS) Cohort, including 561,388 individuals undergoing health examinations during 1985–1996 with a follow-up of >30 years. Methods: Newly diagnosed cases of thyroid cancer were identified from the Swedish Cancer Register. We assessed the associations of nine blood biomarkers of carbohydrate, lipid, and apolipoprotein metabolism measured at the time of health examinations with the subsequent risk of thyroid cancer and demonstrated the temporal trend of these biomarkers during the 30 years before diagnosis of thyroid cancer. Results: After multivariable adjustment, there was a lower risk of thyroid cancer, per standard deviation increase in total cholesterol (TC; HR 0.91; 95%CI 0.82–0.99) and HDL-C (HR 0.86; 95%CI 0.75–0.99). During the 20 to 30 years before diagnosis, patients with thyroid cancer, as a group, demonstrated constantly lower levels of TC and HDL-C, compared to controls. Further, patients with thyroid cancer demonstrated declining levels of these biomarkers during the ten years before diagnosis, whereas controls demonstrated stable or increasing levels. Conclusions: Taken together, we found blood levels of TC and HDL-C to be associated with the risk of thyroid cancer and that there was a declining level of metabolic biomarkers during the 10 years before diagnosis of thyroid cancer.