The network interaction between systemic inflammatory mediators, endothelial cell adhesion function, and adiponectin as mediators of the association between metabolic diseases and periodontitis has not been evaluated. The objective of this study is to assess whether the interaction of baseline serum levels of TNF-α, hs-CRP, ICAM-1, VCAM-1, and adiponectin leads to periodontitis. Five hundred and ninety-seven overweight/obese (overweight: BMI 25 to <30 kg/m2; obese: >30 kg/m2) adults, aged 40–65 years, with complete 3-year follow-up data were included. Generalized structural equation models with negative binomial regression were used to estimate the regression coefficient (β) for the outcome number of teeth with probing pocket depth (PPD) ≥ 4 mm and bleeding on probing (BOP) at 3-year follow-up for a 1 standard deviation unit increase (Δ = +1SD) in each biomarker. After adjusting for multiple covariates, baseline ICAM-1 and VCAM-1 had significant direct effects on increased log-transformed number of teeth with PPD ≥ 4 mm and BOP (β: 0.16; 95% CI: 0.02–0.30; β: 0.15; 95% CI: 0.02–0.30, respectively). Baseline hs-CRP showed a significant indirect effect via ICAM-1 on the log-transformed number of teeth with PPD ≥ 4 mm and BOP (β: 4.84; 95% CI: 0.27–9.42). Thus, elevated serum ICAM-1 and VCAM-1 have a significant direct effect and increased hs-CRP has a significant indirect effect on the predicted level of periodontitis at the 3-year follow-up among overweight/obese Hispanic adults.