Background and Aim: Chemotherapy with drugs such as doxorubicin and trastuzumab in breast cancer patients can lead to cardiotoxicity. Understanding the mechanisms behind this damage is crucial for minimizing side effects and enabling continuation of treatment. The aim of the present study was to investigate the effects of high-intensity interval training (HIIT) and curcumin supplementation on cardiac tissue levels of Galectin-3 and Peroxiredoxin 4 in tumor-bearing rats treated with doxorubicin. Materials and Methods: In this experimental study, 40 female Wistar rats (weighing 18–19 grams) were divided into five groups: (1) Cancer + Doxorubicin, (2) Cancer without drug, (3) Cancer + Doxorubicin + Exercise, (4) Cancer + Doxorubicin + Curcumin, and (5) Cancer + Doxorubicin + Exercise + Curcumin. The HIIT protocol consisted of six intervals at 80–95% VO₂max with active recovery at 30–35% VO₂max, performed for 8 weeks, 5 days per week. Curcumin was administered via gavage at a dose of 100 mg/kg, one hour after each exercise session. Results: Galectin-3 levels were significantly increased in the doxorubicin group, while proxiredoxin-4 levels were significantly decreased in this group (P=0.001). In contrast, in the group that underwent the combined exercise and curcumin intervention, galectin-3 levels were significantly decreased and proxiredoxin-4 levels were significantly increased (P=0.001). Although each of the interventions (exercise or curcumin) alone produced similar effects, the combined effect of the two interventions was much more dramatic. Conclusion: Doxorubicin administration resulted in increased levels of galectin-3 and decreased levels of peroxiredoxin-4 in the heart tissue of cancer-bearing mice. In contrast, the combination of exercise and curcumin had significant protective effects, reducing galectin-3 and increasing peroxiredoxin-4. Although each of these interventions was effective alone, the synergistic effect of their combination was more pronounced.