Objective To assess the diagnostic performance of ultrasound-guided core needle biopsy (CNB) combined with immunohistochemistry (IHC) for distinguishing benign from malignant breast lesions. Methods A retrospective analysis was performed on 82 patients with breast tumors admitted to the Department of Pathology of the First Affiliated Hospital of Henan University of Science and Technology from January 2023 to June 2025. All patients underwent ultrasound-guided CNB followed by surgical excision. Surgical pathology was used as the reference standard. The diagnostic efficacy of CNB alone and CNB combined with IHC was compared by calculating sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV). Agreement with surgical pathology was evaluated using the Kappa statistic, and differences between the 2 diagnostic approaches were analyzed with the McNemar test. Results Compared with CNB alone, CNB combined with IHC yielded higher sensitivity, overall accuracy, and NPV. It also showed better agreement with surgical pathology, with a higher Kappa value. The difference between the 2 approaches was statistically significant (P＜0.05). Conclusion Ultrasound-guided CNB combined with IHC improves the accuracy and consistency of preoperative differentiation between benign and malignant breast lesions. Its value is more evident in morphologically atypical cases, although final interpretation should still be made in the context of clinical and imaging findings.