Background <p>Self-management is vital for patients with diabetic retinopathy (DR) undergoing vitrectomy to reduce complication risks, yet nurse-led tailored support remains insufficient. This study aimed to evaluate the effects of a nurse-led self-management intervention on patients’ self-management, diabetes distress, blood glucose, and postural adherence.</p> Methods <p>The study was a randomized, assessor-blind, two-arm, parallel-group exploratory trial. A total of 120 patients with DR undergoing vitrectomy were randomly assigned to the intervention and control groups. The intervention group received the 6-month nurse-led self-management intervention, while the control group received usual care. Baseline data were collected prior to the intervention (T0). Data on the self-management ability, diabetes distress and blood glucose were measured at 1 month (T1), 3 months (T2) and 6 months (T3) after discharge. Postural adherence was assessed within 7 days after discharge. Evaluation of the intervention manual was conducted prior to discharge, and evaluation of the overall intervention program was conducted at 6 months. Outcomes were compared between groups using generalized estimating equations (GEE) based on the intention-to-treat principle.</p> Results <p>Baseline characteristics showed no statistically significant differences between the two groups. GEE analysis indicated that, compared with the control group, the intervention group demonstrated significantly greater improvements in self-management ability at T1 (β = 5.228, 95% CI: 2.178 to 8.277, <i>P</i> = 0.001), T2 (β = 7.942, 95% CI: 3.978 to 11.905, <i>P</i> &lt; 0.001), and T3 (β = 7.805, 95% CI: 4.021 to 11.589, <i>P</i> &lt; 0.001), as well as significantly greater reductions in diabetes distress at T2 (β = -5.005, 95% CI: -8.307 to -1.702, <i>P</i> = 0.003) and T3 (β = -5.250, 95% CI: -8.566 to -1.934, <i>P</i> = 0.002). Regarding blood glucose, the intervention group showed lower levels at follow-ups, but no significant group×time interaction was found in the primary longitudinal model. Additionally, the intervention group had significantly higher postural adherence scores (Z = -2.005, <i>P</i> = 0.045) than the control group. Most patients in the intervention group evaluated the intervention manual and program positively.</p> Conclusions <p>The nurse-led self-management intervention can effectively improve the self-management ability and postural adherence, and reduce diabetes distress in patients with DR undergoing vitrectomy. However, optimal protocols for blood glucose management remain to be further explored in research. These findings provide valuable guidance for healthcare professionals to improve health outcomes in patients with DR undergoing vitrectomy.</p> Trial registration <p>This study was registered at the Chinese Clinical Trial Registry (clinical trial number: ChiCTR2300067520, date of the registration: 10/01/2023).</p>