Vaccine therapies confer adaptive immunity against specific disease-causing pathogens. Vaccines are usually prepared from a heat-killed form of the pathogens, surface proteins, and toxins produced by the pathogens. These vaccines induce the host immune system to seek and inhibit pathogenic bacteria by stimulating antibody production. The administration of vaccines also enhances the process of antigen presentation, which stimulates specific immune responses in the form of cytokine (including interleukin) production, B-cell differentiation, and T-helper cell function. However, in many cases, vaccines fail to stimulate an immune response. This might be due to several factors such as excess T-regulatory cell secretion, incorrect route of administration, pathogenic mutations, ineffectiveness of standalone adjuvant usage, shorter duration of activity, side effects in patients, and failure to stimulate an immune response despite high antigen dosage. Therefore, probiotics were administered in hosts as a novel strategy for improving oral vaccine-mediated immune response. In the first such case dating back to 1995, Lactobacillus casei GG enhanced antibody production after rotaviral vaccination in infants. Overall, the consumption of probiotics had a variable effect on immunological activity to date. This review is aimed at highlighting the mechanisms by which probiotics affect vaccine-specific immunomodulation. In addition, reasons for probiotic inactivity also are discussed.