Context: The aging phenotype is quite heterogeneous, being the result of the capability of each individual to successfully or unsuccessfully response to stressors. The reduction of homeostatic reserve characterizing aging is accompanied by a remodeling of the endocrine system. Frailty has been indicated as a promising way for capturing the physiological decline as well as the biological aging of the individuals. In particular, the Frailty Index (FI), based on the assumption that health deficits tend to accumulate with aging, represents a quantitative measure of extreme interest. Objective: The study aims to correlate the thyroid hormone levels with FI in a population of centenarians and their offspring to capture the effects of thyroid remodeling in extreme longevity. Study design: The study described 593 well-characterized Italian subjects, including 180 centenarians, as well as 276 centenarian's offspring and 137 age-matched controls. Results: FT3 levels and FT3/FT4 ratio were significantly lower (p < 0.001) and TSH levels higher (p < 0.001) in centenarians compared to the other groups, analysing both overall subjects and excluding subjects with hormone levels out of the normal ranges. In overall centenarians, we observed a negative correlation between FI and FT3 (ρ: −0.281, p < 0.001), FT3/FT4 (ρ: −0.344, p < 0.001) and TSH (ρ: −0.223, p 0.003) and a positive association between FI and FT4 (ρ: 0.189, p = 0.001). In centenarians with hormone levels within the normal ranges, similar negative correlations were observed between FI and FT3 (ρ: −0.201, p = 0.02) and FT3/FT4 (ρ: −0.264, p = 0.002). In this sub-analysis, FI positively correlated with FT4 and age (ρ: 0.167, p = 0.05; ρ: 0.219, p = 0.005, respectively). Conversely, no significant correlations were observed between hormone levels and FI in offspring and controls. Conclusions: We found an association between thyroid hormone levels and frailty in centenarians, underlying the significant role of thyroid in the aging process and longevity.