Objective To investigate the clinical value of combining breast ultrasound with serum fibroblast growth factor receptor 1 (FGFR1) and C-reactive protein (CRP) levels in distinguishing benign from malignant breast masses. Methods A retrospective analysis was conducted on clinical data from 244 patients with breast masses confirmed by surgery or biopsy from January 2018 to June 2023 at Huanghe Sanmenxia Hospital. Patients were divided into benign group (n＝166) and malignant group (n＝78) according to pathological results. General clinical data, serum FGFR1 and CRP levels, and breast ultrasound imaging features were compared between the two groups. The diagnostic performance of breast ultrasound, FGFR1, CRP, and their combination was evaluated using receiver operator characteristic (ROC) curve. Consistency with pathological diagnosis was assessed by Kappa test. Results Serum FGFR1 and CRP levels were significantly higher in the malignant group than those in the benign group (all P＜0.001). Typical malignant ultrasound features, such as rich blood flow, irregular shape, and spiculated margins, were more frequently observed in the malignant group. ROC analysis showed the combined detection of ultrasound, FGFR1, and CRP achieved the highest area under the curve (AUC＝ 0.965), with a sensitivity of 98.72% and accuracy of 91.39%, outperforming single indicators. Kappa analysis indicated the combined test had the best agreement with pathology (Kappa＝0.814, P＜0.001). Conclusion Breast ultrasound combined with serum FGFR1 and CRP detection provides high diagnostic value for differentiating benign and malignant breast masses and can serve as a valuable clinical adjunct diagnostic tool.