Background: Metabolic syndrome (MetS) is a global public health concern, although its association with the inflammatory potential of the diet is still indefinite. The main objective of the present study was to investigate the association of MetS and its components with the inflammatory potential of the diet in a Croatian working population with sedentary occupations. Methods: In a cross-sectional study, Croatian workers (n = 366) self-administrated questionnaires for sociodemographic and health-related data. Their anthropometric measurements and fasting blood samples were collected for evaluation of MetS. The inflammatory potential of the diet was assessed with a Dietary Inflammatory Index (DII)® , scored using dietary data collected from a food frequency questionnaire. Multivariable logistic regression analysis, adjusted for sex, age, body mass index, education, smoking, physical activity and energy intake, was used to establish the association between DII and MetS. Results: MetS prevalence was 25% and was significantly associated with a pro-inflammatory diet [mean (SD) 3.28 (1.45); P < 0.01]. The pro-inflammatory diet was statistically associated with women, university degree, moderate physical activity, snacking between meals, central obesity, hypertriglyceridaemia, hypertension, low high-density lipoprotein-cholesterol, MetS prevalence and lower adherence to a Mediterranean diet. Multivariable logistic regression analysis showed a statistically positive association for a one-unit increase in the DII and MetS prevalence (odds ratio = 2.31; 95% confidence interval = 1.61-3.31; P < 0.01) and hypertension (odds ratio = 1.28; 95% confidence interval = 1.01-1.64; P = 0.04). Conclusions: Further longitudinal studies in different parts of Croatia, including inflammation biomarkers, are needed to enable a more defined view of the inflammatory potential of a diet and its association with various inflammatory-based health conditions. The results obtained in the present study indicate the need for the development of anti-inflammatory dietary interventions for population health protection.