This systematic review with meta-analysis aimed to evaluate the effect of antioxidants as an adjuvant in periodontitis treatment. The following databases were consulted: PubMed, Scopus, Web of Science, Cochrane, Lilacs, OpenGrey, and Google Scholar. Based on the PICO strategy, the inclusion criteria comprised interventional studies including periodontitis patients (participants) treated with conventional therapy and antioxidants (intervention) compared to patients treated only with conventional therapy (control) where the periodontal response (outcome) was evaluated. The risk of bias was evaluated using the Cochrane RoB tool (for randomized studies) and ROBINS-I tool (for nonrandomized studies). Quantitative data were analyzed in five random effects meta-analyses considering the following periodontal parameters: clinical attachment loss (CAL), plaque index (PI), gingival index (GI), bleeding on probing (BOP), and probing depth (PD). After all, the level of certainty was measured with the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) tool. Among the 1884 studies identified, only 15 interventional studies were according to the eligibility criteria and they were included in our review. From them, 4 articles presented a high risk of bias. The meta-analysis showed a statistically significant difference for CAL (SMD 0.29 (0.04, 0.55), p = 0.03, I 2 = 13%), PI (SMD 0.41 (0.18, 0.64), p = 0.0005, I 2 = 47%), and BOP (SMD 0.55 (0.27, 0.83), p = 0.0001, I 2 = 0%). The GRADE tool showed a moderate to high certainty in the quality of evidence depending on the clinical parameter and antioxidants used. These results suggest that the use of antioxidants is an adjunct approach to nonsurgical periodontal therapy which may be helpful in controlling the periodontal status.