Our meta-analysis aimed to evaluate the efficacy of localized sustained-release drugs in periodontitis and comorbid diabetes. PubMed, Cochrane Library, Embase, and Web of Science were comprehensively searched until 4 December 2024, and 10 randomized controlled trials (RCTs) were included. The results indicated that, compared to the control group, localized sustained-release drugs significantly reduced probing depth (PD) (SMD = -0.77, 95% confidence interval [CI] (-1.37, -0.16)) but did not reduce clinical attachment loss (CAL) (SMD = -0.18, 95% CI (-0.60, 0.23)), sites with glycated hemoglobin (HbA1c) (SMD = 0.03, 95% CI (-0.38, 0.43)), plaque index (SMD = -0.37, 95% CI (-0.80, 0.06)), sites with bleeding on probing (BOP) (SMD = -0.26, 95% CI (-0.68, 0.16)), and gingival index (SMD = 0.07, 95% CI (-0.30, 0.44)). Subgroup analysis by different drugs elicited that, compared to the control treatment, chlorhexidine was effective in reducing BOP% (SMD = -0.55, 95% CI (-0.90, -0.19)). Our meta-analysis finds that the efficacy of localized sustained-release drugs in periodontitis and comorbid diabetes is limited.