The aim of this study was to investigate the therapeutic potential of resveratrol in combination with cisplatin on mouse tumor growth in hyperthermal conditions, i.e. the effect of this combination on inhibition of angiogenesis and tumor development, and on macrophage polarization. In addition, it was investigated whether a multimodal approach with hyperthermia and resveratrol could abolish cisplatin resistance in tumor cells through modulation of histone deacetylases (HDAC) activity and heat shock proteins, contributing to direct toxicity on tumor cells. The tumor was induced by injecting 1×106 EAT cells subcutaneously (sc) into the thighs of Swiss albino mice. Mice were treated with resveratrol per os for five consecutive days beginning on day 2 after tumor injection and/or by injecting cisplatin intraperitoneally (ip) at a dose of 2.5 mg/kg on days 10 and 12 and a dose of 5 mg/kg on day 15. Immediately thereafter, mice were exposed to systematic hyperthermia for 15 min at a temperature of 41 °C. Results show that the administration of resveratrol and cisplatin with hyperthermia is an effective approach in tumor therapy. It successfully inhibits angiogenesis and tumor growth and modulates macrophage polarization to the M1 phenotype. Also, it abolishes tumor cells' cisplatin resistance through modulation of HDAC activity and concentration of HSP-70 and HSP-90 chaperones, contributing to the increased lifespan of mice.