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In this study, we conducted a meta-analysis (MA) and systematic review to evaluate the effectiveness of vaccines against post-weaning diarrhea (PWD), caused by enterotoxigenic Escherichia coli (ETEC), in piglets. A Bayesian network meta-analysis (NMA) was also performed to compare the effects of combining different target antigens on vaccine efficacy. Relevant electronic databases were searched using pre-specified search terms, and 17 studies were selected based on three outcomes: diarrhea, mortality, and average daily weight gain (ADWG). In pairwise MA, the vaccinated group showed a significant decrease in diarrhea (OR = 0.124 [0.056, 0.275]) and mortality (OR = 0.273 [0.165, 0.451]), and a significant increase in ADWG (SMD = 0.699 [0.107, 1.290]) compared with those in controls. Furthermore, NMA results showed that all vaccine groups, except for group D (LT enterotoxin), were effective against PWD. Rank probabilities indicated that the F4 + F18 + LT combination was the best regimen for preventing diarrhea (SUCRA score = 0.92) and mortality (SUCRA score = 0.89). NMA also demonstrated that, among the vaccine groups, those inducing simultaneous anti-adhesion and antitoxin immunity had the highest efficacy. Our results provide evidence-based information on the efficacy of vaccines in reducing PWD incidence in pigs and may serve as guidelines for antigen selection for commercial vaccine development in the future.