Background Inflammation plays a major role in the development of metabolic syndrome (MetS) and its progression. Recent studies have shown that pentraxin-3 (PTX-3), osteoprogerin (OPG), and tumor necrosis factor-alpha (TNF-α) are key factors in MetS pathophysiology, but evidence for endorsing their clinical use is currently unclear and insufficient. Aim The study aimed to evaluate the association between the inflammatory biomarkers’ levels and the severity of MetS. Methods The study was observational, transversal, prospective, cohort, and analytical type. We enrolled 80 patients (M:F = 1, mean age = 55 ± 10.77 years) who met MetS criteria. The study protocol included: medical history, physical examination, 6-min walk test distance (6MWTD), biochemical tests, electrocardiogram, echocardiography, and carotid ultrasonography. We also performed plasmatic measurement of PTX-3, OPG, and TNF-α, in addition to standard biochemical tests. Results Subjects with severe MetS had higher values of body mass index (BMI) and waist circumference (p p = 0.001). PTX-3 levels were significantly higher in patients with severe MetS (p = 0.03) and the values were not influenced by age or gender. OPG positively correlated with BMI (r = 0.264, p = 0.018). 6MWTD was lower in patients with severe MetS (p = 0.005), whereas CCA-IMT was higher in this group of patients (p = 0.005). In addition, the receiver operating characteristic (ROC) curve analysis for PTX-3 identified a cut-off value of 10.7 ng/dl that differentiates between mild and severe MetS [AUC 0.656; sensitivity =47.1% (95% CI = 36.1%–62.3%); specificity = 78.9% (95% CI = 54.4%–93.9%)]. Conclusion PTX-3 was correlated with the severity of MetS, with other inflammatory parameters and cardiovascular tests. CCA-IMT and 6MWTD are useful in differentiating between mild and severe MetS.