Oral vaccines are potential options for preventing global pandemics because of their ability to elicit systemic and mucosal immunity and the high degree of compliance among individuals for oral vaccines. Nevertheless, oral vaccine efficacy is insufficient, and there is heterogeneity in the vaccine response among individuals, which may be attributed to the complex network of interactions in the gastrointestinal tract. An increasing amount of evidence suggests that the composition and function of the gut microbiota are essential factors modulating the efficacy of oral vaccines. Deepening our understanding of the implications and potential mechanisms of the interaction between oral vaccines and the gut microbiota could inspire the design of effective oral delivery methods. Here, the effects of the gut microbiota on the mucosal immune system and oral vaccine efficacy are reviewed. Examples and implications for modulating the gut microbiota are also summarized. We hope that this review inspires a focus on oral vaccines and highlights pivotal crosstalk between the gut microbiota and vaccine effectiveness.