Abstract Context Thyroid hormones affect metabolism in various tissues, organs, and systems. However, the overall impact of thyroid function on an individual’s vulnerability to adverse outcomes remains unclear. Objective To investigate the cross-sectional and prospective association of thyroid function with the frailty index, a well-established measure of overall health. Design and Setting The Rotterdam Study, a population-based, prospective cohort study. Participants and Main Outcome Measurements Participants with baseline measurements of thyroid function and the frailty index were eligible. The frailty index was measured at baseline and after a median follow-up time of 10.1 years (interquartile range, 5.7 to 10.8 years). A higher frailty index indicated a worse health state. We assessed the association of thyroid function with frailty at baseline, frailty at follow-up, and frailty changes over time, adjusting for age, sex, cohort, smoking, alcohol, and education. Results We included 9640 participants (mean age, 64.9 years). There was a U-shaped association of thyrotropin (TSH; P < 0.0003) and free thyroxine (FT4; P < 0.0001) with frailty at baseline. There was no association of TSH, but a positive association of FT4 with frailty at follow-up and frailty changes over time (β, 1.22; confidence interval, 0.73 to 1.72 per 1 unit FT4). Conclusion In this population-based study, participants with low and high thyroid function were more likely to be frail than participants with normal thyroid function. However, only those with higher FT4 levels had an increased risk of becoming more frail over time. The identification of FT4 as a potential marker of health deterioration could have future implications regarding the prediction and prevention of frailty.