Abstract Background and Aims Cardiovascular complications are major threats in advanced renal failure and metabolic dysfunction with several unmet medical needs. This study aimed to investigate the therapeutic effects of a special food additive (FLEXOVITAL) in a newly developed mouse model of reno-cardio-metabolic disease, induced by moderate renal failure in combination with a special Western diet. Method Male C57BL/6J mice (4 weeks old, n = 18) were subject to unilateral nephrectomy (UNX), fed a Western diet rich in fat carbohydrates and salt (WD), and were followed for 12 weeks compared with SHAM-operated mice on standard chow (n = 19). One group of UNX+WD mice (n = 8) was fed a food additive (FLEXOVITAL; FLX) containing extracts of Rhodiola rosea, beetroot, and the amino acids arginine and citrulline. Body weight (BW), blood pressure (tail-cuff), endothelial-dependent vasorelaxation (myograph), glucose metabolism (IPGTT), body fat and lean mass composition (DEXA), adipocyte area, renal function (Glomerular Filtration Rate (GFR) by plasma clearance of FITC-inulin), and mitochondrial function (Oroboros, High-resolution respirometry) were measured together with biochemical analysis of heart injury (Troponin-I), inflammation (IL6) and histological analyses of the kidney and heart. Results BW gain was seen in the UNX+WD and SHAM group, and was 25% less in the FLX group (p < 0.05). The fat/lean-mass ratio increased by 17% (p < 0.01) and the adipocyte area by 31% (p < 0.001) in the UNX+WD group but was virtually normalized in the FLX group (p < 0.01). Fasting and non-fasting glucose levels became elevated in the UNX+WD group and were reduced in the FLX group (p < 0.05). Impaired glucose clearance in the UNX+WD group, was partially prevented by FLX. BP significantly increased in the UNX+WD group (MAP = 78 → 90 mmHg, p < 0.001), and was largely prevented by FLX (MAP = 82 mmHg, p < 0.01). Endothelial function was significantly impaired in the UNX+WD group (p < 0.01) and partially preserved in the FLX group (p < 0.05). GFR was reduced by almost 60% in the UNX+WD group but improved with a 75% protective effect in the FLX group (p < 0.05). Significant glomerular injuries with mesangial proliferation were observed in the UNX+WD group (p < 0.001) but were less pronounced in the FLX group (p < 0.01). Tubular injury score (1-10) increased from 1 in SHAM to 6.5 in the UNX+WD group and was partly protected (4.5) in the FLX group (p < 0.05). Troponin-I levels were 15 pg/ml in the SHAM group, markedly increased in the UNX+WD group (p < 0.001), whereas completely reversed in the FLX group (p < 0.01). No significant histological cardiac injuries or deviations could be demonstrated. Inflammatory activity (IL6) increased by 88% in the UNX+WD there was a trend of reduction in mice with FLX. Mitochondrial oxygen efficiency (P/O ratio) was improved in the kidneys of the FLX group compared to the UNX+WD group (p < 0.05). Conclusion In the present multiorgan disease model, significant renal, cardiovascular, and metabolic dysfunction/injuries emerge in mice with a moderate reduction of renal function when fed a Western diet rich in fat, carbohydrates, and salt. Protective effects were noted by dietary FLX treatment in most functional assessments made in the model. This indicates FLX is a potential new treatment in patients with reno-cardio-metabolic disease. The next phase involves confirming these findings in the clinical setting.