Objective This study evaluated the association of serum irisin level with thyroid autoantibody (TAA) positivity and subclinical hypothyroidism (SH). Methods In this cross-sectional study, 334 participants were assigned to one of the following four age- and sex-matched groups: TAA plus SH (84 patients), isolated TAA (83 patients), isolated SH (83 patients), or healthy controls (84 individuals). Irisin and creatine kinase (CK) were measured in serum samples. Results Patients with TAA plus SH, isolated TAA, and isolated SH had higher irisin levels compared with the controls. There was a significant increase in the irisin level in the TAA plus SH group compared with the control group. Among all participants, the irisin levels were positively associated with thyroglobulin and thyroid peroxidase antibody titers and high-density lipoprotein cholesterol levels, but negatively associated with waist circumference, glycated hemoglobin levels, and fasting plasma glucose levels. The irisin level was not associated with the thyroid-stimulating hormone, free thyroxine, or CK levels. Irisin levels were independently associated with TAA, with or without SH, but they were not associated with SH alone. Conclusions Irisin level may help to predict the risk of developing TAA with or without SH.