Objective To evaluate the clinical value of combining the Thyroid Imaging Reporting and Data System (TIRADS) with BRAFV600E gene mutation testing in diagnosing atypical or follicular lesions of undetermined significance (AUS/FLUS) in thyroid nodules. Methods Patients with thyroid nodules (221 cases, 223 nodules) who underwent fine-needle aspiration biopsy and were cytopathologically diagnosed as AUS/FLUS, with surgical pathological confirmation, were selected. All nodules underwent ultrasound examination and were classified according to C-TIRADS and ACR-TIRADS, along with BRAFV600E gene mutation testing. Using postoperative pathological results as the gold standard, receiver operating characteristic (ROC) curves were plotted to analyze the diagnostic performance of each method individually and in combination for distinguishing benign and malignant AUS/FLUS lesions. Results Among the 223 nodules included, 165 were malignant and 58 were benign. ROC curve analysis revealed that the AUC, sensitivity, specificity, and accuracy of BRAFV600E gene mutation testing, C-TIRADS, and ACR-TIRADS alone for diagnosing benign and malignant AUS/FLUS were 0.852, 73.94%, 96.55%, 79.82%; 0.880, 67.27%, 98.28%, 75.34%; and 0.843, 85.45%, 79.31%, 83.86%, respectively. The combination of C-TIRADS and BRAFV600E testing yielded an AUC, sensitivity, specificity, and accuracy of 0.950, 90.91%, 96.55%, and 88.3%, respectively, while the combination of ACR-TIRADS and BRAFV600E testing resulted in 0.937, 95.76%, 79.31%, and 82.96%, respectively. The combination of BRAFV600E testing and C-TIRADS significantly improved sensitivity and accuracy without significantly reducing specificity compared to BRAFV600E or C-TIRADS alone (P < 0.05). Similarly, the combination of BRAFV600E testing and ACR-TIRADS significantly enhanced sensitivity compared to BRAFV600E or ACR-TIRADS alone (P < 0.001). Conclusion The combination of TIRADS and BRAFV600E gene mutation testing demonstrates strong diagnostic performance for AUS/FLUS, offering significant clinical value.