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Objective: The aim of this study was to evaluate the clinical value of preoperative thyroid autoantibodies with reference to the post‐thyroidectomy patient pathology. Design: A retrospective cohort study. Setting: Two tertiary care academic hospitals. Materials and Methods: A total of (n = 473) subjects who underwent thyroidectomy from 2009 to 2019 were included. Preoperative serum thyroid autoantibodies (anti‐thyroglobulin [anti‐Tg] and anti‐thyroperoxidase [anti‐TPO]) were measured, and the potential predictors of postoperative pathological diagnosis (age, gender, and thyroid autoantibodies) were assessed using multivariable regression models. Results: Patients with positive thyroid autoantibodies were more likely to have malignant disease than benign disease; adjusted odds ratio (AOR) = 1.6 (1.3–2.7, p = 0.002) for anti‐Tg, and AOR = 1.6 (1.1–2.5, p = 0.027) for anti‐TPO. A subset analysis of the same predictors performed on patients with cancer (malignant vs. microcarcinoma) showed that patients with ages ≥40 were more likely to develop microcarcinoma as opposed to malignant disease; AOR = 1.8 (1.1–3.1, p = 0.03) for anti‐TPO, and AOR = 1.7 (1.0–2.9, p = 0.04) for anti‐Tg. Conclusion: Preoperative thyroid autoantibodies could be used clinically to predict the risk of malignancy in thyroid nodules, thus helping guide treatment decisions in patients with thyroid nodules and speeding up the decision to undergo surgical intervention. [ABSTRACT FROM AUTHOR]