Objectives: To investigate the association between peripheral blood monocyte levels and the prevalence as well as the severity of Diabetic Kidney Disease (DKD) in patients with diabetes mellitus, using data from the NHANES 2005-2016 database. Methods: This cross-sectional study used data from the NHANES 2005-2016 database, including 6,062 diabetic patients aged 20-80 with complete demographic and clinical data. DKD was identified according to the 'KDIGO 2021 Guidelines', with monocyte levels assessed using the Beckman Coulter method. Albuminuria and eGFR (CKD-EPI) defined DKD severity. Statistical analyses incorporated sampling weights and used logistic regression to assess the association between monocyte levels and DKD, adjusting for other confounding factors. Results: We analyzed demographics and clinical characteristics across three monocyte level groups. Individuals in the highest monocyte level group tended to be older, predominantly male, and current smokers, and had higher BMI, leukocyte count, triglycerides, and UACR, but lower total cholesterol, LDL, HDL, and eGFR levels (all P < 0.05). Elevated monocyte levels were linked to increased CKD risk, evidenced by eGFR and UACR, and associated with dyslipidemia. In multivariate logistic regression analysis, after adjusting for age, gender, smoking, duration of diabetes, BMI, SBP, glucose lowering agents, HbA1c, and dyslipidemia, we found a positive association between peripheral monocyte levels and the prevalence of CKD (OR=1.93, P value=0.022). In addition, there was a negative association between monocyte levels and eGFR (β=-7.68, P value < 0.01). However, no significant association was found between monocyte levels and log-transformed UACR (β=0.12, P value=0.156). Conclusions: In conclusion, our study emphasizes an association between elevated monocyte levels and increased prevalence and severity of DKD, suggesting a potential role of monocytes in DKD's pathophysiology. However, the limitations of our study including the inability to establish causality due to its cross-sectional design and the potential biases inherent in self-reported data.