Abstract Background Accurate diagnosis of unexplained cervical lymphadenopathy (CLA) using medical images heavily relies on the experience of radiologists, which is even worse for CLA patients in underdeveloped countries and regions, because of lack of expertise and reliable medical history. This study aimed to develop a deep learning (DL) radiomics model based on B-mode and color Doppler ultrasound images for assisting radiologists to improve their diagnoses of the etiology of unexplained CLA. Methods Patients with unexplained CLA who received ultrasound examinations from three hospitals located in underdeveloped areas of China were retrospectively enrolled. They were all pathologically confirmed with reactive hyperplasia, tuberculous lymphadenitis, lymphoma, or metastatic carcinoma. By mimicking the diagnosis logic of radiologists, three DL sub-models were developed to achieve the primary diagnosis of benign and malignant, the secondary diagnosis of reactive hyperplasia and tuberculous lymphadenitis in benign candidates, and of lymphoma and metastatic carcinoma in malignant candidates, respectively. Then, a CLA hierarchical diagnostic model (CLA-HDM) integrating all sub-models was proposed to classify the specific etiology of each unexplained CLA. The assistant effectiveness of CLA-HDM was assessed by comparing six radiologists between without and with using the DL-based classification and heatmap guidance. Results A total of 763 patients with unexplained CLA were enrolled and were split into the training cohort (n=395), internal testing cohort (n=171), and external testing cohorts 1 (n=105) and 2 (n=92). The CLA-HDM for diagnosing four common etiologies of unexplained CLA achieved AUCs of 0.873 (95% CI: 0.838–0.908), 0.837 (95% CI: 0.789–0.889), and 0.840 (95% CI: 0.789–0.898) in the three testing cohorts, respectively, which was systematically more accurate than all the participating radiologists. With its assistance, the accuracy, sensitivity, and specificity of six radiologists with different levels of experience were generally improved, reducing the false-negative rate of 2.2–10% and the false-positive rate of 0.7–3.1%. Conclusions Multi-cohort testing demonstrated our DL model integrating dual-modality ultrasound images achieved accurate diagnosis of unexplained CLA. With its assistance, the gap between radiologists with different levels of experience was narrowed, which is potentially of great significance for benefiting CLA patients in underdeveloped countries and regions worldwide.