Purpose <p>This study aimed to compare peripapillary OCTA parameters between eyes with no diabetic retinopathy (NDR) and those with non-proliferative diabetic retinopathy (NPDR), and to investigate their independent associations with NPDR status.</p> Methods <p>This cross-sectional study enrolled 128 healthy controls and 116 patients with type 2 diabetes mellitus. Diabetic eyes were categorized into the NDR group (<i>n</i> = 41 eyes) and mild, moderate, and severe NPDR groups (<i>n</i> = 32, 23, and 20 eyes, respectively). All subjects underwent peripapillary OCTA scanning. We quantitatively analyzed nerve fiber layer vascular plexus vessel density (NFLVPVD) and superficial vascular plexus vessel density (SVPVD), as well as peripapillary retinal nerve fiber layer (pRNFL) thickness. Baseline characteristics and OCTA quantitative parameters were compared across the control, NDR, and three NPDR subgroups. Multivariable-adjusted logistic regression was then performed to examine the association between peripapillary OCTA parameters and NPDR.</p> Results <p>Compared with the NDR group, NFLVPVD, SVPVD, inferior 3-mm pRNFL thickness, and superior 6-mm pRNFL thickness were significantly lower in the pooled NPDR group (all <i>P</i> &lt; 0.05). In multivariable-adjusted binary logistic regression, higher NFLVPVD was independently associated with lower odds of NPDR (OR = 0.884, 95% CI: 0.800–0.977, <i>P</i> = 0.016).</p> Conclusions <p>Peripapillary NFLVPVD is independently associated with lower odds of NPDR.</p>