AIM: Circulating platelets are essential in hemostasis, thrombosis, and immune responses. Modifications in platelet function may impact immunological reactions to dental biofilm and cardiovascular health. Understanding changes in platelet status and activity in patients with periodontitis is still a subject of investigation. This study aimed to synthesize evidence from observational studies that investigated platelet status and activity in patients with and without periodontitis. METHODS: MEDLINE-PubMed, EMBASE, and Cochrane-CENTRAL Library databases were searched up to November 2024. Primary outcomes included platelet count (PC) and mean platelet volume (MPV). Secondary outcomes encompassed any other biomarker relevant to platelet status and activity. Methodological quality was evaluated using the Newcastle-Ottawa scale, and heterogeneity was analyzed. Descriptive analysis of outcomes and meta-analysis, incorporating trial sequential analysis of PC and MPV, were conducted. The body of evidence was graded by utilizing the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). RESULTS: 3621 unique records were identified, resulting in 23 eligible studies with 22 variables evaluating the platelet status. Fourteen studies exhibited a low risk of bias, and 9 exhibited moderate risk of bias. PC in patients with periodontitis was significantly higher compared to individuals without periodontitis (Mean Difference (MD) = 23.55 ×10 CONCLUSIONS: The certainty is moderate for slightly higher PC in patients with periodontitis compared to individuals without it and low for no difference in MPV between the two groups. The evidence is not robust to claim a clear difference in other platelet activation biomarkers between the two groups. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) by number: CRD42023439051.