Aim: To assess the differential clinical response to step 2 of periodontal therapy and repeated subgingival instrumentation between teeth with suprabony and intrabony defects. Methods: Electronic and manual search were performed to identify studies reporting the differential clinical outcomes of non-surgical periodontal therapy (NSPT) in presence or absence of intrabony defects. The Cochrane Risk of Bias 2 and the Newcastle Ottawa scale were used to assess the risk of bias. Results: Two thousand three hundred forty-eight articles were initially screened, and a total of 5 articles were finally included. Regarding the primary outcome measure, two studies reported PPD reduction values at 6 months after step 2 of periodontal therapy, showing an opposite response of intrabony defects compared to suprabony defects (3.2 mm ± 1.9 versus 2.2 mm ± 1.7 and 0.48 mm ± 0.42 versus 0.72 mm ± 0.36, respectively), while one study reported no differences at 3 months. One study showed a negative association between the presence of intrabony defect and PPD reduction at 9 months after non-surgical step 3 (p < 0.05). Conclusion: Due to the limited number of studies and heterogeneity of the data, conflicting evidence emerged for the differential response to NSPT of intrabony and suprabony defects.