BACKGROUND: Exclusive enteral nutrition (EEN) is recommended as first-line induction therapy for pediatric Crohn's disease (CD), but its use in adults, especially alongside biologics, is limited. This study evaluated the effectiveness of a structured oral EEN approach combined with biologics as induction therapy in adult active CD. METHODS: A total of 242 biologically treated adult CD patients were retrospectively enrolled after propensity score matching and divided into combined-EEN (n = 121) and non-EEN (n = 121) groups. Clinical and endoscopic outcomes, body composition, pharmacokinetics, and cytokine levels were assessed. RESULTS: The combined-EEN group showed superior outcomes, with higher endoscopic response (69.4 % vs. 37.2 %, P < 0.001) and remission rates (36.4 % vs. 21.5 %, P = 0.011). They also demonstrated improved skeletal muscle index (P = 0.038) and normalized fat distribution. Infliximab concentrations were higher in this group (3.3 vs. 1.7 mg/dl, P = 0.048), and levels of IL-1beta, IL-6, and TNF-alpha were significantly reduced (all P < 0.05). CONCLUSIONS: EEN combined with biologics enhances induction therapy outcomes in adult CD, contributing to improved body composition recovery, optimized pharmacokinetics of biologics, and reduced levels of inflammatory cytokines. These findings support the broader implementation of EEN in adult CD management and warrant further validation in multicenter clinical trials.