Objectives <p>To investigate the role of super-resolution contrast-enhanced ultrasound (SR-CEUS) in evaluating inflammatory activity in Crohn’s disease (CD).</p> Materials and methods <p>In this prospective study, we consecutively enrolled CD patients confirmed by clinical and ileocolonoscopic findings. All patients underwent B-mode ultrasound (BMUS), color Doppler flow imaging (CDFI), CEUS, and SR-CEUS within 1 week of ileocolonoscopy. SR-CEUS quantitative parameters were recorded, with simple endoscopic score for Crohn’s disease (SES-CD) as the reference standard. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis.</p> Results <p>52 consecutive CD patients were categorized into active (SES-CD ≥ 3, <i>n</i> = 30) and inactive (SES-CD &lt; 3, <i>n</i> = 22) groups. SR-CEUS clearly visualized the intramural microvascular architecture of the bowel wall. SR-CEUS yielded an AUC of 0.903 with 86.4% sensitivity (95% CI: 66.7–95.3%), and 86.7% specificity (95% CI: 70.3–94.5%) for assessing inflammatory activity, significantly outperforming both CDFI (<i>p</i> = 0.014) and CEUS (<i>p</i> = 0.045), while showing no statistically significant difference in comparison with BMUS (<i>p</i> = 0.988). Furthermore, the combination of BMUS and SR-CEUS achieved an AUC of 0.967 for diagnosing active CD, with 100% sensitivity&#xa0;(95% CI: 85.1–100%) and 86.7% specificity&#xa0;(95% CI: 70.3–94.7%), which was significantly superior to BMUS alone (<i>p</i> = 0.038).</p> Conclusions <p>SR-CEUS provides quantitative microvascular perfusion maps that display vascular density, flow velocity, and direction, offering a non-invasive tool for evaluating inflammatory activity in CD.</p> Critical relevance statement <p>This study demonstrates that super-resolution contrast-enhanced ultrasound (SR-CEUS) provides a novel, non-invasive approach for quantitative evaluation of inflammatory activity in Crohn’s disease (CD), which serves as a valuable supplement or alternative to endoscopy in routine monitoring.</p> Key Points <p><UnorderedList Mark="Bullet"> <ItemContent> <p>An unmet need remains for accurate, non-invasive tools to assess CD activity.</p> </ItemContent> <ItemContent> <p>SR-CEUS outperforms conventional CDFI and CEUS in distinguishing active from inactive CD.</p> </ItemContent> <ItemContent> <p>Combining SR-CEUS with standard BMUS yields excellent diagnostic accuracy, establishing this combined approach as a promising non-invasive alternative for monitoring inflammatory activity in CD patients.</p> </ItemContent> </UnorderedList></p> Graphical Abstract <p></p>