This review explores the bidirectional relationship between the human microbiome and SARS-CoV-2 infection, elucidating its implications for COVID-19 susceptibility, severity, and therapeutic strategies. Metagenomic analyses reveal notable alterations in microbiome composition associated with SARS-CoV-2 infection, impacting disease severity and clinical outcomes. Dysbiosis within the respiratory, gastrointestinal, oral, and skin microbiomes exacerbates COVID-19 pathology through immune dysregulation and inflammatory pathways. Understanding these microbial shifts is pivotal for devising targeted therapeutic interventions. Notably, co-infection of oral pathogens with SARS-CoV-2 worsens lung pathology, while gut microbiome dysbiosis influences viral susceptibility and severity. Potential therapeutic approaches targeting the microbiome include probiotics, antimicrobial agents, and immunomodulatory strategies. This review underscores the importance of elucidating host-microbiota interactions to advance precision medicine and public health initiatives in combating COVID-19 and other infectious diseases.