Objective To investigate the diagnostic value of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammatory body and sphingosine-1-phosphate (S1P) in early diabetic nephropathy and its progression. Methods A total of 600 diabetic patients who were treated in Shaanxi Provincial People’s Hospital between January 2018 and December 2020 were selected, and the patients were divided into simple diabetes group, early diabetic nephropathy group and clinical diabetic nephropathy group. The expression of NLRP3 messenger RNA (mRNA) in fasting venous blood mononuclear cells was detected by real-time fluorescence quantitative polymerase chain reaction, and the level of S1P was detected by enzyme-linked immunosorbent assay double-antibody sandwich method. Pearson correlation analysis was used to explore the correlation between blood NLRP3 mRNA and S1P levels. The receiver operating characteristic curve was used to evaluate the diagnostic value of blood NLRP3 mRNA and S1P levels in early diabetic nephropathy and clinical diabetic nephropathy. Results Among the 600 diabetic patients, 205 were in the simple diabetes group, 198 in the early diabetic nephropathy group and 197 in the clinical diabetic nephropathy group. There was no significant difference in age and gender among the three groups (P>0.05). The blood levels of NLRP3 mRNA and S1P in the clinical diabetic nephropathy group were higher than those in the early diabetic nephropathy group and the simple diabetes group, the blood NLRP3 mRNA and S1P levels in the early diabetic nephropathy group were higher than those in the simple diabetes group. The differences were statistically significant, and the blood NLRP3 mRNA levels of the three groups were 2.69±0.64 vs. 2.05±0.56 vs. 1.76±0.51, and the S1P levels were (1.49±0.27) vs. (1.16±0.13) vs. (0.89±0.07) μmol/L (P<0.05). There was a positive correlation between blood NLRP3 mRNA and S1P level in patients (r=0.455, P<0.001). Blood NLRP3 mRNA, S1P levels and their combined detection can be used to diagnose whether diabetic patients develop early diabetic nephropathy (area under the receiver operating characteristic curve were 0.645, 0.968, 0.971; P<0.001) and whether it progressed to clinical diabetic nephropathy (area under the receiver operating characteristic curve were 0.825, 0.918, and 0.945; P<0.001). Conclusion Blood NLRP3 mRNA and S1P levels can be used to diagnose early diabetic nephropathy and evaluate its disease progression.