Although various treatments are developed against COVID-19 variants, probiotic, and synbiotic adjunct therapy with several benefits such as safety, low cost, and availability could be needed for preventing or treating COVID-19 infection. The present systematic review aimed to assess the prophylactic efficacy of the probiotic, prebiotic, and synbiotic administration against COVID-19. The protocol of this systematic review was registered at the PROSPERO (Code number: CRD42023418900). The Scopus, Cochrane Library, Web of Sciences, and PubMed databases were systematically searched to define the clinical trials published up to November 2022 in the English language. The comparison of the incidence of COVID-19 disease and levels of specific antibodies against SARS-cov2 between the intervention and placebo groups were evaluated in this systematic review. According to the five included trials, four indicated the incidence of COVID-19, and no significant differences were observed between the probiotic and placebo groups during 1, 2, or 3 months of follow-up in the mentioned studies. Regarding the antibody assays against SARS-Cov2 including IgM, IgG, or IgA reported by three eligible trials, there were no significant differences between the intervention and control groups. It seems that the administration of single or multi-strain probiotics or synbiotics had no prophylactic effects in different populations such as high-risk staff exposed to COVID-19, elderly nursing home residents, healthy adults, and household contact with COVID-19 patients during 1-to-3-months of intervention.