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Background: Regular physical activity and diet can be effective in preventing cardiovascular disease. Therefore, the purpose of this study was to investigate the effect of 6 weeks of high intensity interval training (HIIT) with nano-curcumin supplementation on factors related to cardiovascular disease such as lipid profile and C-reactive protein (hs-CRP) in overweight girls. Materials and Methods: The research method was randomized-experimental with pre-post test design. 48 overweight student girls with mean age of 21.78±0.94 years and BMI equals 28.12±2.1kg/m2 were randomly divided into four groups: training (n=12), training-supplement (n=12), supplement (n=12) and control group (n=12). Supplement groups consumed a 80 mg nano-curcumin capsule daily. Training groups performed an exercise protocol of HIIT training with maximum heart rate for 6 weeks (three sessions per week). The control group did not have any regular exercise. Blood samples were obtained for measurement of lipid profile serum levels (Low Density Lipoprotein (LDL), Total Cholesterol (TC), Triglyceride (TG) and High-Density Lipoprotein (HDL)) and CRP before and after a 6-week period of exercise and supplementation. Data were analyzed by ANOVA and dependent t-test at P≤0.05. Results: In the supplement-training group, triglyceride (P=0.03) and CRP (P=0.03) significantly decreased, HDL (P=0.034) significantly increased and LDL and cholesterol did not show significant changes (P≥0.05). But there were no significant changes in lipid profile and CRP in the training and supplement groups (P≥0.05). Conclusion: HIIT training and nano-curcumin supplementation alone resulted in slight positive changes of lipid profile and CRP. But it seems that doing HIIT training together with nano-curcumin supplementation has a reinforcing effect on each other and they are more effective at preventing cardiovascular diseases.