Increasing evidence shows that some probiotics can improve vaccine responses as adjuvants. This study aimed to evaluate the effect of Pediococcus pentosaceus MIANGUAN (PPM) on SARS-CoV-2 vaccine-elicited immune response in mice. Six-week-old female ICR mice were primed and boosted with SARS-CoV-2 vaccine intramuscularly at weeks 0 and 4, respectively. Mice were gavaged with PPM (5 × 10 CFU/mouse) or PBS (control) for 3 days immediately after boosting vaccination. Compared to the control, oral PPM administration resulted in significantly higher levels of RBD-specific IgG binding antibodies (> 2.3-fold) and RBD-specific IgG1 binding antibodies (> 4-fold) in the serum. Additionally, PPM-treated mice had higher titers of RBD-specific IgG binding antibodies (> 2.29-fold) and neutralization antibodies (> 1.6-fold) in the lung compared to the control mice. The transcriptional analyses showed that the B cell receptor (BCR) signaling pathway was upregulated in both splenocytes and BAL cells in the PPM group vs. the control group. In addition, the number of IFN-γ-producing splenocytes (mainly in CD4 + T cells as determined by flow cytometry) in response to restimulation of RBD peptides was significantly increased in the PPM group. RNA sequencing showed that the genes associated with T cell activation and maturation and MHC class II pathway (CD4, H2-DMa, H2-DMb1, H2-Oa, Ctss) were upregulated, suggesting that oral administration of PPM may enhance CD4 + T cell responses through MHC class II pathway. Furthermore, PPM administration could downregulate the expression level of proinflammatory genes. To conclude, oral administration of PPM could boost SARS-CoV-2 vaccine efficacy through enhancing the specific humoral and cellular immunity response and decrease the expression of inflammation pathways.