Contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) has been used in the differential diagnosis of benign and malignant tumors by visualization of tumor microcirculation and perfusion. However, its diagnostic role in submucosal tumors (SMTs), especially leiomyomas and gastric submucosal tumors (GISTs) was rarely studied. The aim of this study was to analyze the diagnostic role of CEH-EUS for SMTs (<50 mm) and the value of assessing the malignant potential of GISTs. We retrospectively included patients with tumors <50 mm in diameter who underwent preoperative EUS and CEH-EUS examination and had pathologically confirmed as leiomyomas and GISTs. To analyze the imaging features of CEH-EUS with pathological diagnosis as the gold standard and evaluate its diagnostic value. This study included 10 cases of leiomyomas and 38 cases of GISTs. Under CEH-EUS detection, 86.9% of GISTs showed hyper-enhancement, 89.5% showed diffuse enhancement, 39.5% showed non-enhancing spots, and 97.4% showed obvious capsule enhancement. In contrast, the leiomyoma cases mostly showed hypo-enhancement (50.0%) or non-enhancement (30.0%) (p < 0.05). Then, the value of CEH-EUS in the differential diagnosis of benign and malignant tumors based on blood flow is significantly higher than that of B-EUS. Signal appearance time was significantly faster in the intermediate-high risk GISTs than in the very low-low risk group (5.1 s versus 15.5 s, p < 0.05), and the AUROC values predicted the risk at this time to be 0.903 (0.763-0.975). Heterogeneous perfusion and non-enhancing spots were also more common in the intermediate-high risk group. Univariate and multivariate analysis revealed that intratumoral irregularitie was an independent predictor of moderate to high risk (OR 3.99, 95%CI 1.04-90.95), with sensitivity, specificity and accuracy of 73.33%, 91.30% and 84.21%, respectively. Through this study, CEH-EUS has a good differential diagnostic ability for leiomyomas and GISTs, and has a high value in predicting the risk of GISTs.