The human microbiome plays a significant role in health and disease, and its composition is influenced not only by infectious diseases but also by therapeutic interventions such as antibiotic therapy, with conditions such as COVID-19 having an even greater impact on microbiome composition. This study investigated the effects of COVID-19 and antibiotics on microbiome alpha diversity, beta diversity, and taxonomic composition in different human sample types (saliva, subgingival plaque, supragingival plaque, and tongue swabs). There were significant differences in microbial richness and evenness. The control groups presented the highest diversity (Shannon index ~ 1.5–2.0), indicating a balanced and stable microbiome. The Covid_antibio group had the lowest diversity (~0.5–1.0), indicating dysbiosis from antibiotics. Bray-Curtis beta diversity analysis, visualized via NMDS and PCoA plots, highlighted distinct microbial community structures across groups. The control groups presented broader dispersion, indicative of high variability, whereas the Covid_antibio groups clustered tightly, suggesting reduced variability and dominance of opportunistic taxa. PERMANOVA confirmed significant differences in microbial composition between groups (F-value = 1.6428, R2 = 0.25427, p = 0.016). Taxonomic composition analysis at the phylum level revealed a dominance of Actinobacteriota, Firmicutes, and Proteobacteria in all the groups, with a marked increase in Proteobacteria in the Covid_antibio samples. At the genus level, the control groups were enriched with commensals such as Streptococcus and Prevotella, whereas the Covid and Covid_antibio groups presented higher abundances of opportunistic taxa such as Neisseria and Haemophilus, reflecting the compounded effects of disease and antibiotics. These findings emphasize the significant disruptions in microbial diversity and composition caused by COVID-19, which are exacerbated by antibiotics. The results highlight the importance of preserving microbial diversity in disease states, particularly through judicious antibiotic use and microbiome-supportive interventions such as probiotics. Future studies should further explore the functional implications of these microbial shifts and their long-term effects on health and recovery.