Purpose <p>We aimed to compare the diagnostic performance of [⁶⁸Ga]Ga-FAPI-04 PET/CT, [¹⁸F]F-FDG PET/CT, enterography and intestinal ultrasound (IUS) in detecting inflamed segments in patients with Crohn’s disease (CD), as well as in identifying CD-related complications.</p> Methods <p>This prospective study enrolled 16 patients with CD. Each patient underwent [⁶⁸Ga]Ga-FAPI-04 PET/CT, [¹⁸F]F-FDG PET/CT, enterography, and IUS within 14&#xa0;days. Using endoscopic results as the reference standard, we assessed the diagnostic accuracy and agreement across these imaging modalities for detecting segmental lesions in the proximal upper gastrointestinal (GI) tract and ileocolon. Their performance in identifying CD-associated complications and mesenteric changes was also evaluated.</p> Results <p>[⁶⁸Ga]Ga-FAPI-04 PET/CT exhibited high sensitivity (73.3%, 95% CI: 0.610–0.829), specificity (97.8%, 95% CI: 0.887–0.996) and accuracy (84.0%, 95% CI: 0.758–0.897) for detecting segmental lesions in the terminal ileum and colon. These performance metrics were comparable to those of enterography, [¹⁸F]F-FDG PET/CT and IUS (all <i>P</i> &gt; 0.05), with nearly perfect diagnostic agreement observed among these imaging modalities (all κ &gt; 0.81; all <i>P</i> &lt; 0.001). In the upper GI tract and proximal small intestine, its sensitivity (53.8%, 95% CI:0.291–0.768), specificity (92.1%, 95% CI:0.792–0.973) and accuracy (82.4%, 95% CI:0.697–0.904) were similar to [¹⁸F]F-FDG PET/CT and enterography, with good diagnostic agreement (both κ = 0.73; <i>P</i> &lt; 0.001). However, its resolution was suboptimal for detecting mild lesions. Notably, [⁶⁸Ga]Ga-FAPI-04 PET/CT outperformed other imaging methods in detection rate and sensitivity for identifying CD-associated complications and mesenteric changes.</p> Conclusion <p>[⁶⁸Ga]Ga-FAPI-04 PET/CT may sever as a one-step, non-invasive diagnostic option for CD patients.</p>