Combining antibiotics with non-surgical periodontal therapy has a beneficial impact in case of infection while its role for dental-related outcomes is still unclear. The current study's main objective was to evaluate the impact of adding adjuvant systemic and topical antimicrobial therapy to non-surgical periodontal therapy. A systematic literature search was accomplished and 1,093 study participants with periodontal diseases were recruited to the current study; 541 of them were treated with adjuvant systemic or topical antimicrobial agents and 552 with non-surgical interventions. The inclusion criteria of the current study took into account only randomized clinical trials. Adding systemic antibiotics to non-surgical intervention resulted in a significant enhancement regarding probing pocket depth reduction (PPD). Metronidazole/amoxicillin showed a significant impact on PPD and the clinical attachment level (CAL), while doxycycline showed no significant impact regarding CAL. Using topical antimicrobial agents showed a significant beneficial role in reducing PPD regarding doxycycline, while non-significant effects were seen with metronidazole. Adding adjuvant systemic and topical antimicrobial agents to non-surgical periodontal therapy showed a beneficial impact regarding PPD and CAL (metronidazole/amoxicillin and doxycycline). In addition, using doxycycline as a topical agent showed a beneficial impact on the reduction of PPD.