Background: Periodontitis, a prevalent chronic inflammatory disease, offers insights into the broader landscape of chronic inflammatory conditions. The progression and treatment outcomes of periodontitis are closely related to the oral microbiota’s composition. Adjunctive systemic Amoxicillin 500 mg and Metronidazole 400 mg, often prescribed thrice daily for 7 days to enhance periodontal therapy’s efficacy, have lasting effects on the oral microbiome. However, the precise mechanism through which the oral microbiome influences clinical outcomes in periodontitis patients remains debated. This investigation explores the pivotal role of the oral microbiome's composition in mediating the outcomes of adjunctive systemic antibiotic treatment. Methods: Subgingival plaque samples from 10 periodontally healthy and 163 periodontitis patients from a randomized clinical trial on periodontal therapy were analyzed. Patients received either adjunctive amoxicillin/metronidazole or a placebo after mechanical periodontal treatment. Microbial samples were collected at various intervals up to 26 months post-therapy. Using topic models, we identified microbial communities associated with normobiotic and dysbiotic states, validated with 86 external and 40 internal samples. Logistic regression models evaluated the association between these microbial communities and clinical periodontitis parameters. A Directed Acyclic Graph (DAG) determined the mediating role of oral microbiota in the causal path of antibiotic treatment effects on clinical outcomes. Results: We identified clear distinctions between dysbiotic and normobiotic microbial communities, differentiating healthy from periodontitis subjects. Dysbiotic states consistently associated with below median %Pocket Probing Depth ≥ 5 mm (OR = 1.26, 95% CI [1.14–1.42]) and %Bleeding on Probing (OR = 1.09, 95% CI [1.00–1.18]). Factors like microbial response to treatment, smoking, and age were predictors of clinical attachment loss progression, whereas sex and antibiotic treatment were not. Further, we showed that the oral microbial treatment response plays a crucial role in the causal effect of antibiotic treatment on clinical treatment outcomes. Conclusions: The shift towards a normobiotic subgingival microbiome, primarily induced by adjunctive antibiotics, underscores the potential for microbiome-targeted interventions to enhance therapeutic efficacy in chronic inflammatory conditions. This study reaffirms the importance of understanding the oral microbiome's role in periodontal health and paves the way for future research exploring personalized treatment strategies based on individual microbiome profiles.