Introduction <p>Type 2 diabetes mellitus (T2DM) imposes significant challenges, particularly for women, due to psychosocial and cultural factors affecting self-care. Psycho-spiritual interventions integrating psychological and spiritual support show promise in enhancing diabetes management. This randomized controlled trial (RCT) evaluated a psycho-spiritual care program’s impact on medication adherence, self-management, and glycemic control in women with T2DM. The study addresses a gap in rigorous, gender-specific RCTs for holistic diabetes care.</p> Methods <p>This single-blinded RCT enrolled 140 women with T2DM (aged 18–65) from an outpatient clinic in Bandarabbas, randomized 1:1 to intervention or control groups, stratified by age and baseline HbA1c. The intervention group received an 8-week psycho-spiritual program combining cognitive-behavioral therapy, mindfulness, and spiritual practices (e.g., prayer, gratitude journaling) tailored to cultural beliefs. The control group received enhanced routine diabetes education. Outcomes were assessed at baseline, post-intervention (week 8), and 2-month follow-up (week 16) using the Morisky Medication Adherence Scale (MMAS-8), Diabetes Self-Management Questionnaire (DSMQ), and HbA1c levels. Linear mixed-effects models analyzed group-by-time interactions, adjusting for baseline covariates. Missing data were handled using last observation carried forward (LOCF) in intent-to-treat analysis.</p> Results <p>Of 140 participants, 134 completed the study (66 intervention, 68 control). Baseline characteristics were similar except for diabetes duration (<i>p</i> = 0.03) and BMI (<i>p</i> = 0.04), adjusted in analyses. The intervention group showed significant improvements in MMAS-8 scores (<i>p</i> &lt; 0.001, Cohen’s d = 1.35 post-intervention; d = 1.38 at follow-up) and DSMQ scores (<i>p</i> &lt; 0.001, d = 1.79 post-intervention; d = 1.66 at follow-up) compared to controls. HbA1c reduction was significant at follow-up (<i>p</i> &lt; 0.001, d = 1.02), but not immediately post-intervention (<i>p</i> = 0.59). Group-by-time interactions were significant for MMAS-8 (F(2,264) = 10.89, <i>p</i> &lt; 0.001), DSMQ (F(2,264) = 13.12, <i>p</i> &lt; 0.001), and HbA1c (F(2,264) = 6.45, <i>p</i> = 0.002). Sensitivity analyses confirmed robustness. Large effect sizes underscored the intervention’s efficacy.</p> Conclusion <p>The psycho-spiritual care program significantly improved medication adherence, self-management, and glycemic control in women with T2DM. These findings support integrating psychological and spiritual components into diabetes care. Future research should explore long-term sustainability and generalizability across diverse populations.</p> Trial registration <p>The study was registered at the Iranian Registry of Clinical Trials (IRCT); trial registration number: IRCT20220704055367N6; available at <a href="https://irct.behdasht.gov.ir/">https://irct.behdasht.gov.ir/</a>, registered on 2025-01-11.</p>