Many systematic reviews and meta-analysis have indicated beneficial effects of adjunctive systemic antibiotics in periodontal therapy in specific situations. However, some essential issues such as the ideal time of their administration during periodontal therapy remain unanswered. This systematic review aimed to determine at which phase of periodontal treatment would adjunctive systemic antibiotics lead to the best clinical outcomes, during the active phase or in the reevaluation phase. Searches in the databases Medline, Scopus and Cochrane Library were conducted. The randomized clinical trials and retrospective cohort studies comparing the clinical benefits of adjunctive systemic antibiotic administration in the active phase of periodontal treatment versus their administration in the reevaluation phase were included. The primary outcomes assessed were differences in clinical changes in periodontal pocket depth and clinical attachment loss at all post-treatment phases. Of the 6209 records identified, two randomized clinical trials and two retrospective cohort studies were eligible according to inclusion criteria. Two studies suggested there were greater clinical benefits when systemic antibiotics were prescribed during the active phase of periodontal therapy than in the reevaluation phase while two other studies showed no significant difference in clinical outcomes at 6 months between these two different timing of administration. The evidence available and evaluated in this systematic review is of heterogeneous quality and limited by the restricted number of studies and their dissimilarities in their study design and outcome reporting. Despite insufficient evidence to determine the ideal time to the adjunctive systemic antibiotic administration in the periodontal therapy, it seems that prescription of systemic antibiotic at the active phase of periodontal therapy leads to better clinical outcomes.