Scope Excessive visceral adipose tissue (VAT) is associated with higher secretion of pro‐inflammatory molecules, contributing to systemic inflammation and obesity‐related metabolic disturbances. Methods and results This prospective analysis includes 117 overweight/obese adults (55–75 years) from the PREDIMED‐Plus study. Fourteen inflammatory markers and adipokines are measured using a Bio‐Plex assay with multiplex technology: insulin, glucagon, IL‐6, visfatin, ghrelin, GLP‐1, TNF‐α, MCP‐1, PAI‐1, resistin, C‐peptide, leptin, adipsin, and adiponectin. Participants are categorized into tertiles according to changes in VAT after 1‐year of follow‐up, determined by dual‐energy X‐Ray absorptiometry. Participants allocate in tertile 3, which represent an increase of VAT content after 1‐year of follow‐up compared to tertile 1, show significant differences in insulin (T3 vs T1, fully adjusted model: p = 0.037, p for trend 0.042), PAI‐1 (fully adjusted model: p = 0.05, p for trend 0.06), c‐peptide (fully adjusted model: p = 0.037, p for trend 0.042), and TNF‐α (fully adjusted model p = 0.037, p for trend 0.042). Conclusion The results evidence that a reduction in VAT is associated with clinical improvements in several inflammatory and adiposity markers, mainly in insulin, c‐peptide, and PAI‐1 levels, and these improvements may contribute to a reduction in cardiometabolic disturbances observe in obesity. Excessive visceral adipose tissue (VAT) is associated with inflammation. Our results evidence that a reduction in VAT is associated with improvements in inflammatory and adiposity markers in participants with metabolic syndrome.