AimsThis study aimed to assess the variability and treatment effect heterogeneity in response to non‐surgical periodontal therapy (NSPT).MethodsData from randomized controlled trials included in two recent systematic reviews on the effect of NSPT on mean clinical attachment loss (CAL), mean probing pocket depth (PPD), percentage of sites with bleeding on probing (%BOP), PPD ≤3 mm (%PD ≤3 mm), and C‐reactive protein levels (CRP) at 3–12‐month follow‐up among adults with systemic diseases or conditions were used. In these trials, the control arms received no treatment, hygiene advice, or supragingival scaling. The Bayesian meta‐regression models were utilized to assess the variability ratios between NSPT and control groups.ResultsData from 36 trials on mean PPD, 32 trials on mean CAL, eight trials on %PD ≤3 mm, 31 trials on %BOP and 19 trials on CRP were used. Variability in mean CAL and CRP was approximately 10% higher in the NSPT arms than in the control arms, hinting that there may be room for treatment effect heterogeneity. Instead, variability in mean PPD, %BOP, and %PD ≤3 mm was lower in the NSPT arms than in the control arms.ConclusionPotential treatment effect heterogeneity in response to NSPT was observed for CRP and mean CAL. However, substantial measurement error in CAL and natural variation in CRP may contribute to these findings. Conversely, treatment effect heterogeneity appears less pronounced for mean PPD, %BOP, and %PD ≤3 mm, potentially due to greater treatment effects in patients with more severe periodontitis and reduced measurement error in these parameters.