Background and Introduction: The utilization of combined exercise interventions and natural supplement supplementation is currently emphasized as a novel strategy for modulating inflammatory markers and enhancing metabolic health in high-risk populations. The present study aimed to examine the combined effect of HIIT and curcumin supplementation on plasma levels of irisin and selected inflammatory markers (Interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), Tumor Necrosis Factor-alpha (TNF-α)) along with body composition in sedentary middle-aged women. Materials and Methods: In this quasi-experimental study, 80 healthy volunteer women (aged 40-60 years) were randomly assigned to four groups: training + supplement, training + placebo, supplement (500 mg/day), and placebo. The HIIT protocol was implemented for eight weeks (three sessions per week). Blood samples were collected after 12 hours of fasting, both 48 hours before and after the intervention. The study followed a double-blind design, and data were analyzed using repeated measures ANOVA with between-group factors, followed by Tukey's post-hoc test at a significance level of α<0.05. Results: In the post-test phase, irisin levels were significantly higher in training + supplement (p=0.001), training + placebo (p=0.02), and supplement (p=0.03) groups compared to the placebo group. The CRP level demonstrated a significant decrease in the training + supplement group relative to the training + placebo (p=0.001), supplement (p=0.001), and placebo groups (p=0.001). Furthermore, the training + placebo (p=0.001) and supplement (p=0.002) groups showed lower CRP levels than the placebo group. Regarding IL-6, both the training + supplement (p=0.01) and supplement (p=0.01) groups exhibited a significant reduction compared to the placebo group. TNF-α levels were also significantly lower in the training + supplement (p=0.001), training + placebo (p=0.012), and supplement (p=0.010) groups compared to the placebo group. Conclusion: The combination of HIIT with curcumin supplementation synergistically improves metabolic indices, reduces inflammation, and decreases body fat percentage in middle-aged women.