Abstarct: Introduction: Type 2 diabetes mellitus is one of the most prevalent mextabolic disorders worldwide, with cardiovascular complications being the leading cause of mortality in these patients. Endothelial dysfunction, particularly reduced nitric oxide (NO) bioavailability, is recognized as the first and most key event in the pathogenesis of diabetic vascular complications. Postmenopausal women with type 2 diabetes are among the most vulnerable populations to cardiovascular diseases due to estrogen decline, increased oxidative stress, and systemic inflammation. High-fat meals also exacerbate endothelial dysfunction by inducing postprandial lipemia. Aerobic exercise and natural supplements with antioxidant and anti-inflammatory properties have been proposed as promising non-pharmacological interventions; however, a direct comparison of the acute effects of these two interventions in the aforementioned population has not been fully investigated. Study Design: The present study was a randomized, double-blind, crossover clinical trial. Thirteen postmenopausal women with type 2 diabetes (age 45–65 years, menopause duration >4 years, HbA1c >7%, BMI from normal to class I obesity, and without regular physical activity) were randomly assigned to four intervention conditions: 1) supplement + high-fat meal + exercise, 2) placebo + high-fat meal + exercise, 3) placebo + high-fat meal, and 4) supplement + high-fat meal. The exercise intervention consisted of a single 60-minute treadmill walking session at 60% of heart rate reserve, performed 12 hours before the high-fat meal consumption. The supplement intervention involved the consumption of 350 mL of Aloe vera water containing acemannan polysaccharide simultaneously with the high-fat meal. The standard high-fat meal was calculated and provided baxsed on each individual's fat-free mass. Plasma nitrite/nitrate levels (NOx), as an indirect indicator of nitric oxide (NO) bioavailability, were measured at three time points: baxseline, 2 hours, and 4 hours after the high-fat meal consumption, using the Griess method and ELISA kit, respectively. For data analysis in this study, SPSS statistical software version 26 was used. All analyses were performed at a significance level of 0.05. Descxriptive statistics including mean and standard deviation for quantitative variables and frequency and percentage for qualitative variables were calculated. Given the four-condition crossover design and repeated measurement of the dependent variable at three time points, data analysis was performed using repeated measures ANOVA with a 2×2×3 design (supplement × exercise × time). In case of significant interaction effects, simple effects analysis and pairwise comparisons with Bonferroni correction were used to determine the source of the interaction. Results: The findings showed that the main effect of acute aerobic exercise on plasma nitrite/nitrate levels was significant (P=0.001), and this increasing effect remained stable throughout the 4 hours after the high-fat meal. The main effect of Aloe vera-acemannan supplementation alone was not significant (P=0.104), but the interaction effect of supplement × time was significant (P=0.047); such that the supplement at 4 hours after the high-fat meal maintained NOx levels significantly higher than placebo (P=0.007). The interaction effect of supplement × exercise (P=0.614) and the main effect of time (P=0.717) were not significant. Simple effects analysis at T3 showed that both supplement (P=0.007) and exercise (P=0.006) independently affected NOx, but the effect of the supplement was more pronounced in the absence of exercise (P=0.003) compared to its presence (P=0.349). Conclusion: It appears that Aloe vera-acemannan supplementation and acute aerobic exercise affect nitric oxide bioavailability through similar or overlapping pathways. In the presence of exercise, the supplement has no additive effect, but in the absence of exercise, the supplement plays an important protective role in preventing the decline of NOx induced by the high-fat meal. Therefore, for postmenopausal women with type 2 diabetes who are unable to perform regular exercise, consuming Aloe vera-acemannan supplementation along with high-fat meals can be considered as an alternative and accessible strategy to maintain endothelial function and reduce the risk of cardiovascular complications.