Background/Objectives: Direct comparative data for infliximab and vedolizumab are limited due to lack of head-to-head trials. This systematic review and meta-analysis compared the efficacy and safety of infliximab and vedolizumab as intravenous or subcutaneous maintenance treatments for adults with moderately to severely active Crohn's disease or ulcerative colitis. Methods: Medical databases, PubMed, Embase, and the Cochrane Library were systematically searched from January 2010 to May 2024 to identify Phase 1 to 3 randomized controlled trials. The primary and co-primary outcomes were the proportions of patients achieving clinical remission and clinical response at one year, respectively. Safety was also analyzed (PROSPERO CRD42023483599). Data for each outcome were pooled using a two-sided random-effects model in separate analyses for Crohn's disease and ulcerative colitis. Results: Seven eligible Crohn's disease trials and eight eligible ulcerative colitis trials contributed data for 1910 and 2372 patients, respectively. For Crohn's disease, higher proportions of infliximab-treated patients achieved clinical remission (0.64 [95% confidence interval: 0.60-0.68]) and/or clinical response (0.71 [0.67-0.75]) at one year compared with vedolizumab-treated patients (0.40 [0.35-0.46] and 0.47 [0.43-0.51], respectively). For ulcerative colitis, similar proportions of infliximab- and vedolizumab-treated patients achieved clinical remission (0.54 [0.38-0.71] vs. 0.40 [0.35-0.44]) and/or clinical response (0.52 [0.45-0.58] vs. 0.58 [0.51-0.65]) at one year. Safety results showed no significant differences. Conclusions: An indirect comparison of maintenance treatment with infliximab and vedolizumab demonstrated that infliximab yields significantly better efficacy than vedolizumab in Crohn's disease, whereas both agents yielded similar efficacy in ulcerative colitis.