Background: Anthracycline and trastuzumab are essential adjuvant therapies for a variety of cancers, particularly breast, and gastric and esophageal cancers. Whilst prolonging cancer-related survival, these agents can induce drug-related cardiotoxicity. Cardioprotective agents used to mitigate cardiotoxicity, such as angiotensin antagonists, angiotensin receptor blockers and beta‐blockers, are often poorly tolerated in these patients due to intravascular volume fluctuations, which are further escalated by the hemodynamic side effects of these agents. Spiruline, Reishi and Moringa are nutaceuticals with anti-inflammatory effects that are currently used in cancer patients to improve quality of life and fatigue. We hypothesize that the combination of Spirulina, Reishi and Moringa could reduce inflammation and cardiotoxicity of anthracyclines and trastuzumab. Methods: Human cardiomyocytes were exposed to subclinical concentration of doxorubicin and trastuzumab (200 nM) alone or in combination with a formulation composed by Spiruline, Reishi and Moringa (at 10, 25 and 50 µg/ml) for 48h. Cell viability, apoptosis and necrosis were performed. Quantification of malondialdehyde and intracellular Ca2+ were performed through spectrophotometric methods. Anti-inflammatory studies were also performed (expression of NLRP3, TLR4/MyD88 pathways, nuclear expression of NF-kB). Intracellular concentration of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL17-α were also performed. Results: Spiruline, Reishi and Moringa in combination increased synergistically the cell viability during exposure to doxorubicin and trastuzumab. The nutraceutical formulation reduces intracellular Ca2+ overload (-48,8% vs cells treated only to anticancer drugs; p < 0,001), lipid peroxidation (- 47,2 % compared to cells exposed only to anticancer drugs; p < 0,001). The expression of MyD88 and NLRP3 inflammasome were also reduced (-36,3 and -28,58 % vs cells exposed only to anticancer drugs, respectively; p < 0.001). Notably, Spiruline, Reishi and Moringa increased of 26,3% the production of IL-10 and IL-2. Cytokines involved in cardiotoxicity and chemoresistance were reduced, such as IL-1α and IL-1β (-18,3 and -27,4 % vs DOXO-TRA group), IL-6 (-31,2 % vs DOXO-TRA group) and IL17-α (-27,3 % vs DOXO-TRA group) (p < 0.01 for all). Conclusions: During exposure to doxorubicin and trastuzumab, the combination of Spiruline, Reishi and Moringa exerts cardioprotective and anti-inflammatory effects. Their properties are mediated by the reduction of iCa2+ content that consequently reduces lipid peroxidation and the expression of NLRP3- MyD88. These results indicating the potential use of this nutraceutical formulation in preclinical models of anthracycline and anti HER2 antibodies-mediated cardiotoxicity.