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Introduction Accurate differentiation of benign and malignant thyroid nodules is critical for appropriate management. Fine-needle aspiration cytology (FNAC), although valuable, has limitations, especially in follicular-patterned neoplasms. Galectin-3, a beta-galactoside-binding lectin involved in cell proliferation and apoptosis, has been proposed as a diagnostic immunohistochemical marker. This study evaluates the utility of galectin-3 in distinguishing malignant from non-malignant nodular thyroid lesions. Methods A prospective observational study was conducted on 56 female patients undergoing thyroidectomy. Histopathological evaluation categorized cases into the benign (n=25), borderline (n=6), and malignant (n=25) groups. Immunohistochemical staining for galectin-3 was performed on paraffin-embedded tissue sections. Positivity was defined by cytoplasmic and/or nuclear staining. Results Galectin-3 expression was observed in 66.7% (14/21) of malignant lesions, predominantly in classic papillary thyroid carcinoma. None of the benign or borderline cases exhibited galectin-3 positivity. Notably, other papillary carcinoma variants were also negative. Statistical analysis showed a significant correlation between galectin-3 expression and malignancy (p < 0.001). Conclusion Galectin-3 is a highly specific immunohistochemical marker for malignant thyroid lesions, particularly classic papillary thyroid carcinoma. Its absence in benign and borderline lesions highlights its diagnostic value. Incorporating galectin-3 into routine histopathological evaluation can improve diagnostic accuracy, especially in indeterminate or follicular-patterned thyroid neoplasms.