Background <p>There is limited data on the efficacy and safety of combination therapy of dual biologics or small molecules combined with biologics in inflammatory bowel disease (IBD) patients in China. The present retrospective study determined the efficacy and safety of these combinations in Chinese IBD patients.</p> Methods <p>Combination therapy is defined as the simultaneous use of two biologics or one biologic combined with a small molecule drug. The demographic data, laboratory test results, disease characteristics, and adverse events were recorded. Treatment efficacy was evaluated based on clinical response and remission, and endoscopic response and remission, according to the Patient-Reported Outcome-2 system, Simplified Endoscopic Score-Crohn’s Disease system, Mayo score, and Mayo Endoscopic Score. Safety was determined based on the occurrence of adverse events.</p> Results <p>Twenty-three Crohn’s disease and five ulcerative colitis patients underwent combination therapy. The most common combination therapy was vedolizumab combined with ustekinumab (20/28, 71.40%). Based on the intention-to-treat analysis, the overall clinical response rate was 22/28 (78.60%), and 16/28 (57.10%) patients achieved clinical remission. Among the 14 patients who underwent endoscopic evaluation, nine (64.30%) patients achieved endoscopic response, including seven (77.78%) patients who further achieved endoscopic remission. After treatment, C-reactive protein significantly decreased (8.10 [3.50–14.00] to 3.30 [2.20–8.80], <i>p</i> &lt; 0.05), and albumin significantly increased (35.40 [33.80–40.00] to 41.10 [38.30–44.50], <i>p</i> &lt; 0.05). No severe adverse events were reported.</p> Conclusions <p>Combination therapy with biologics or small molecules demonstrates favorable potential in managing refractory IBD, and offers a viable treatment option for Chinese patients. However, further research is needed for validation.</p>