Background <p>Small intestinal endoscopic ultrasonography (SIEUS) enables the comprehensive analysis of the origin and sonographic characteristics of protruding submucosal lesions. Current evidence is limited to case reports. We aimed to investigate the application value of SIEUS for protruding lesions of the small intestine.</p> Methods <p>Clinical data of patients who underwent double-balloon enteroscopy combined with SIEUS at the Sixth Affiliated Hospital of Sun Yat-Sen University between January 2023 and December 2024 were retrospectively collected. A total of 28 patients had concurrently received a diagnosis of protruding lesions of the small intestine and pathological results during their first visit. SIEUS findings were compared with the pathological results.</p> Results <p>Patient cases included stromal tumor (<i>n</i> = 10), ectopic pancreas (<i>n</i> = 7), hemangioma (<i>n</i> = 5), lipoma (<i>n</i> = 3), neuroendocrine tumor (<i>n</i> = 2), and invaginated Meckel’s diverticulum (<i>n</i> = 1). All cases were initially detected via white light endoscopy (WLE) and subsequently characterized by endoscopic ultrasonography during the first visit. Pathological specimens were obtained for all lesions through biopsy, endoscopic minimally invasive surgery, or surgery. Our results indicated 100% diagnostic agreement (28/28) between endoscopic ultrasonography and pathology findings.</p> Conclusion <p>The combination of WLE and SIEUS provides a comprehensive assessment of protruding lesions, with WLE enabling detection and SIEUS facilitating detailed submucosal characterization.</p>