Background: We aimed to assess the association between DII and PD and the mediation effect of DII in the association of PD with systemic inflammation. Using the National Health and Nutrition Examination Survey (NHANES) 2009-2010, 2011-2012 and 2013-2014, participants that received periodontal exam and provided dietary recall data were included. The inflammatory potential of diet was calculated via DII. Periodontitis was defined according to the 2012 case definition. The clinical outcomes of interest were mean periodontal probing (PPD), mean clinical attachment loss (CAL) and thresholds of PPD and CAL. White blood cells (WBC), segmented neutrophils and C-reactive protein (CRP) were used as proxies for systemic inflammation. The periodontal measures were regressed across DII values using adjusted multivariate linear regression. Adjusted mediation analysis appraised the influence of DII in the association of periodontitis and systemic inflammation. 10,178 participants were included. DII was significantly correlated with mean PPD, mean CAL, thresholds of PPD and CAL, WBC, segmented neutrophils and DII (p<0.01). A linear regression logistic adjusted for multiple confounding variables confirmed the association between DII and mean PPD (B = 0.02, Standard Error [SE]: 0.02, p<0.001) and CAL (B = -0.02, SE: 0.01, p<0.001). The association of mean PPD and mean CAL with both white blood cells and segmented neutrophils were mediated by DII (from 2.1 to 3.5%, p<0.001). In the 2009-2010 subset, the association of mean CAL with serum CRP was mediated by DII (52.0%, p<0.01). In conclusion, inflammatory diet and PD may be associated. Also, the inflammatory diet significantly mediated the association of leukocyte counts and systemic inflammation with periodontitis.