Background <p>The Naples prognostic score (NPS) is a new assessment tool. The link between NPS and mortality in patients with diabetes mellitus (DM) is unknown. Compared with traditional single biomarkers, NPS innovatively incorporates the nutritional and inflammatory status of DM patients into a unified assessment system to stratify risk for DM patients in a more detailed manner.</p> Objective <p>We therefore investigated the correlation of NPS with the risk of all-cause mortality (ACM) and cardiovascular mortality (CVM) in DM patients.</p> Methods <p>This study used data on DM patients from the NHANES 2001–2018, while the National Death Index (NDI) was searched for mortality data until December 31, 2019. The correlation of NPS with ACM and CVM in DM patients was analyzed using a Kaplan–Meier survival curve (K-M curve) and a multivariate Cox regression model. Subgroup analysis was conducted to verify consistency.</p> Results <p>Follow-up data showed 388 all-cause deaths and 132 cardiovascular deaths in the study population. The K-M curve indicates significantly different survivals in different NPS groups (<i>p</i> &lt; 0.05). Higher mortality risk (all causes: HR = 2.68, 95% CI = 1.46–4.93; cardiovascular disease (CVD): HR = 3.53, 95% CI = 1.43–8.72) was observed in the high NPS group (with a score of 3–4) versus the low NPS group (with a score of 0). Similarly, subgroup analysis by age, gender, and race showed a higher risk of ACM and CVM in DM patients with high NPS (3–4 scores).</p> Conclusion <p>This study found a significant positive correlation of NPS with the risk of ACM and CVM in DM patients.</p>