The aims of this cross-sectional study were to explore the ability of serum interleukin 18 (IL-18) and adiponectin to identify metabolic syndrome (MetS), and to verify their association with an index of central lipid overaccumulation (lipid accumulation product (LAP)) and cardiometabolic risk factors in a population of middle-aged Brazilian men. A group of 218 apparently healthy middle-aged Brazilian men (age, 50.3 ± 4.97 years) underwent anthropometric, clinical, sociodemographic, and standard serum biochemical assessments. LAP was calculated and the study participants were categorized into 3 groups according to serum IL-18 and adiponectin cut-points tertiles to verify the association of these biomarkers with cardiometabolic risk factors. The MetS group had more less active (p = 0.03) and obese (p < 0.01) individuals who exhibited higher IL-18 (p < 0.01) and lower adiponectin (p < 0.01) than did those in the group with no MetS. After adjustments (age, smoking, alcohol consumption, physical activity level, and total body fat), serum IL-18 ≥ 336.4 pg/mL was an independent factor for MetS occurrence and it was directly associated with LAP (≥51.28), central obesity, hypertriglyceridemia, and hypertension (p < 0.05), but not with high-density lipoprotein cholesterol (HDL-C). Serum adiponectin ≥ 7.02 μg/mL was negatively associated with MetS occurrence, LAP, hypertriglyceridemia, and low HDL-C (p < 0.05), but not with central obesity and hypertension. In conclusion, both IL-18 and adiponectin demonstrated the ability to identify MetS in this population, with IL-18 being more accurate. The association of these biomamarkers with LAP and cardiometabolic risk factors highlights its relevance as a diagnostic tool.