Ustekinumab and vedolizumab are both effective for treating Crohn's disease (CD). However, no head-to-head trials have been conducted thus far. We aimed to compare the effectiveness of ustekinumab and vedolizumab in CD patients either naïve or exposed to tumor necrosis factor-alpha inhibitors (TNFi).Patients treated with vedolizumab or ustekinumab for luminal CD were included from six centers in China from May 2020 to July 2023. Steroid-free remission, clinical remission, objective response, and remission at Weeks 26 and 52 were evaluated in a retrospective multicenter propensity score-weighted cohort.A total of 536 patients were included (386 ustekinumab, and 150 vedolizumab). After adjustment, ustekinumab showed higher rates of clinical remission (56.4% vs. 47.8%, P = 0.005), steroid-free remission (55.4% vs. 46.1%, P = 0.003), and objective response (67.8% vs. 42.7%, P < 0.001) than vedolizumab at Week 26. At Week 52, ustekinumab exhibited significantly higher rates of clinical remission (65.8% vs. 37.5%, P < 0.001), steroid-free remission (65.8% vs. 37.5%, P < 0.001), objective response (66.7% vs. 23.8%, P < 0.001), and objective remission (31.4% vs. 12.7%, P < 0.001). Subgroup analyses revealed that ustekinumab had higher rates of clinical remission, steroid-free remission, and objective response at Weeks 26 and 52, and objective remission at Week 52 in TNFi-exposed patients, while ustekinumab showed higher rates of objective response at Weeks 26 and 52 and clinical remission, steroid-free remission and objective remission at Week 52 in TNFi-naïve patients. Adverse event rates were similar between the groups (4.9% ustekinumab vs. 6.7% vedolizumab, P = 0.423).Ustekinumab showed superior clinical and objective outcomes compared to vedolizumab, with comparable safety outcomes. The therapeutic superiority was observed in both short-term and long-term phases in TNFi-exposed patients, and the long-term phase in TNFi-naïve patients.National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, Key Research Projects of the Sixth Affiliated Hospital, Sun Yat-sen University, the program of Guangdong Provincial Clinical Research Center for Digestive Diseases, and National Key Clinical Discipline.© 2023 The Authors.