The human oral and gut microbiomes play critical roles in maintaining overall health, with growing evidence linking their dysbiosis to a range of systemic diseases. While systemic antibiotics are frequently prescribed perioperatively in dental procedures, their impact on microbiota composition and diversity remains inadequately characterized. This study investigates the effects of prophylactic antibiotics on fecal and oral microbiota in adult patients undergoing periodontal and implant-related dental surgeries. Saliva and stool samples were collected from each subject (N = 64) at five time points – before, during, and after antibiotic administration (days 0, 3, 10, 30, and 90). Microbial diversity and composition were assessed using 16S rRNA sequencing. Shotgun metagenomics was applied to a subset of samples to evaluate changes in antimicrobial resistance genes (ARGs). Significant declines in alpha diversity were observed in both oral and fecal microbiomes, most notably at days 3 and 10, with near recovery by day 90. The oral microbiome exhibited greater alpha and beta diversity disruption compared to the gut, suggesting higher susceptibility to antibiotic-associated disturbance. Patient-level factors including gender, race, gastroesophageal reflux disease/gastric acid suppression, and antibiotic type influenced baseline diversity, disruption, and recovery. Taxonomic analyses revealed that key health-associated genera such as Faecalibacterium, Blautia, and Ruminococcus in the gut, and Streptococcus and Rothia in the oral cavity, were significantly altered post-antibiotic treatment. Notably, some ARGs increased in relative abundance over time, indicating potential long-term ecological consequences of prophylactic antibiotic use. These findings highlight the dynamic response of the human microbiome to antibiotic exposure and underscore the importance of antibiotic stewardship in dental practice. Consideration of individual patient factors, including comorbidities and reported antibiotic allergies, is essential to minimize unnecessary disruption of the microbiome and mitigate the risk of resistance development. Further research on functional outcomes and host-microbiome interactions is warranted to optimize perioperative care in dentistry.