This study is aimed at assessing the association between serum lycopene and its isomers with diabetic kidney disease (DKD) in order patients with diabetes mellitus (DM). Utilizing a cross-sectional design, data were extracted from the National Health and Nutrition Examination Surveys (NHANES) cycles 2003-2006 and 2017-2018. Metrics including serum lycopene, urinary albumin to creatinine ratio, and estimated glomerular filtration rate were collected. Weighted univariate and multivariate logistic regression models were conducted to explore the associations between serum lycopene isomers and DKD in order patients with DM. Subgroup analyses were conducted by different genders, complications, and medical history. A total of 960 order patients with DM were included, of whom 470 (48.96%) had DKD. After covariate adjustment, we found a cis-lycopene concentration range of 8.60-13.19 mu g/dL (Q1-Q2) was associated with lower odds of DKD (OR = 0.53, 95% CI: 0.28-0.98). This association was particularly evident among males (OR = 0.48, 95% CI: 0.25-0.93), patients with a history of hypertension (OR = 0.48, 95% CI: 0.24-0.97), patients with dyslipidemia (OR = 0.52, 95% CI: 0.27-0.99), and those without the angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) use (OR = 0.55, 95% CI; 0.31-0.99). No significant associations were observed between total lycopene, translycopene, and DKD. These findings suggest serum cis-lycopene may be a potential modifiable biomarker for DKD prevention in high-risk elderly populations. Concentrations may improve renal health among the elderly DM patients. Maintaining optimal cis-lycopene levels through dietary interventions may complement conventional renoprotective strategies. Further prospective studies are warranted to establish causal relationships and evaluate targeted lycopene supplementation regimens.