Porcine epidemic diarrhea (PED) continues to inflict devastating losses on global swine production. By systematically reviewing and meta-analysing 32 high-quality studies, we quantified the protective efficacy of PED vaccines and dissected how core variables shape that protection. Using fecal scores as the endpoint, we pooled effect sizes under a random-effects model and explored sources of heterogeneity through subgroup analyses. This analysis showed a pooled effect size (Hedges’ g) of −5.80, confirming that vaccination markedly alleviates diarrheal severity. Moreover, substantial heterogeneity was detected across studies. Stratified analyses revealed that vaccine type, vaccination target, vaccination route, and vaccination frequency are the principal sources of variation, all of which significantly influence vaccine efficacy. Conventional inactivated or live-attenuated formulations still dominate the field, but recombinant live-viral platforms are emerging. Piglets and sows represent the most responsive immunological targets. A two-dose regimen consistently outperforms a single injection, and delivery via intranasal, oral or intramuscular routes offers distinct advantages that can be exploited to maximise mucosal and systemic immunity. Overall, the optimal impact on PED prevention and control is achieved when the vaccine is correctly chosen and paired with an appropriate immunization protocol and delivery route.