Background: Thyroid nodules are common, yet only a small proportion are malignant. The independent role of nodule size in malignancy risk remains debated, particularly after adjustment for clinical, biochemical, and sonographic features. Methods: A retrospective cohort study was conducted on adult patients with thyroid nodules evaluated between 2018 and 2025 at a tertiary care center. Clinical, laboratory, ultrasound, cytology, and histopathology data were extracted. Thyroid-stimulating hormone (TSH), free thyroxine (free T4), and sonographic characteristics were analyzed. Univariable and multivariable logistic regression were performed. Missing ultrasound data were addressed using multiple imputation (m = 20), with pooled estimates derived using Rubin’s rules. The final multivariable model included 446 patients. Results: A total of 446 patients were included, of whom 91 (20.4%) had thyroid malignancy. Malignant nodules were significantly larger than benign nodules (2.30 [1.80] cm vs. 1.80 [1.13] cm; p = 0.015). In univariable analysis, TSH, free T4, and multiple ultrasound features were associated with malignancy. In multivariable analysis, nodule size remained the strongest independent predictor of malignancy (adjusted odds ratio [aOR] 1.51; p < 0.001). Hypoechogenicity (aOR 2.07; p = 0.020) and microcalcifications (aOR 1.86; p = 0.047) also remained independently significant, whereas thyroid function parameters were not associated with malignancy after adjustment. Conclusions: Thyroid nodule size is the strongest independent predictor of malignancy, with select ultrasound features retaining additional predictive value. These findings support incorporating nodule size more prominently into thyroid cancer risk stratification while maintaining key sonographic features.