[Background] The water and soil of Wentang hot spring in Yichun is rich in selenium. In this study, a selenium-rich yeast strain was isolated from this natural selenium-rich area. [Objective] To optimize the culture conditions of the selenium-rich yeast strain and study the protective effect of this strain on cardiac function. [Methods] Sixty typical soil samples were collected, from which a yeast strain with high selenium was screened out on the plate with antibiotics. Microscopy and scanning electron microscopy showed that the isolate was a typical yeast strain. The strain was identified by 18S sequencing as Hanseniasporauvarum. The addition amount and time of sodium selenate, fermentation time, and fermentation temperature were optimized to improve the selenium content in this strain. The further scale-up fermentation in a fermenter showed a high level of organic selenium content, and the cell density (OD600) reached 132 after 56 h. Furthermore, a mouse model of cardiac hypertrophy was established with doxorubicin to study the physiological function of selenium-rich yeast. [Results] The selenium-rich yeast strain alleviated myocardial hypertrophy, which may be related to its anti-oxidation and anti-apoptosis effects. [Conclusion] We successfully isolated a yeast strain with high selenium content. The culture condition optimization and scale-up fermentation in a 5-L fermenter showed that the obtained yeast strain had a broad industrial application prospect, and such selenium-rich yeast had a strong antioxidant activity.