Two inflammatory mediators—CXCL10 chemokine and interferon-gamma—emerge as key drivers of the rare myocarditis observed with COVID-19 mRNA vaccines, particularly after second doses in young males. Neutralizing these cytokines in mouse models significantly reduced cardiac injury markers and inflammatory gene expression, while the soy isoflavone genistein showed protective effects in both lab-grown heart cells and vaccinated mice. This mechanistic insight represents a crucial advance in vaccine safety research, offering the first clear molecular targets for preventing mRNA vaccine-associated cardiac inflammation. The findings bridge an important gap between the known clinical pattern of post-vaccination myocarditis and its underlying biology. While mRNA vaccines remain overwhelmingly safe and effective, this research provides a pathway for enhancing future vaccine formulations or developing preventive interventions for high-risk individuals. The genistein findings are particularly intriguing, given its established cardiovascular benefits and availability as a dietary supplement. However, the work remains preclinical—human trials would be needed to validate whether cytokine inhibition or genistein supplementation could safely prevent vaccine myocarditis without compromising immune responses. The research also raises questions about individual susceptibility factors that predispose certain people to this inflammatory cascade.