Post-Acute Infection Syndrome (PAIS) is a relatively new medical terminology that represents prolonged sequelae symptoms after acute infection by numerous pathogenic agents. Imposing a substantial public health burden worldwide, PASC (post-acute sequelae of COVID-19 infection) and ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) are two of the most recognized and prevalent PAIS conditions. The presences of prior infections and similar symptom profiles in PAIS reflect a plausible common etiopathogenesis. The human microbiome is known to play an essential role in health and disease. In this review, we reviewed and summarized available research on oral and gut microbiota alterations in patients with different infections or PAIS conditions. We discussed key theories about the associations between microbiome dysbiosis and PAIS disease development, aiming to explore the mechanistic roles and potential functions the microbiome may have in the process. Additionally, we discuss the areas of knowledge gaps and propose the potential clinical applications of the microbiome for prevention and treatment of PAIS conditions.