Atmospheric cold plasma is a powerful and profitable microbial decontamination technology in the food industry. The microbial load and food matrix have a great influence on the plasma inactivation effect. This study aimed to quantify the effects of initial cell concentration and soluble solids on the inactivation of yeast in apple juice by gas-phase surface discharge plasma. A computer simulation model was developed to predict the inactivation process using commercial finite element software, COMSOL Multiphysics, and the model was verified by experiments. Studies have shown that the inactivation of yeast was affected by the initial cell concentration and soluble solids. These effects were quantified by fitting equations and used as model inputs. The simulation model predicted the D-value of plasma inactivation of yeast under different discharge voltages and apple juice volume, which was verified in experiments. Therefore, the established model can be used for plasma development to predict how the food matrix affects the inactivation process, thereby providing useful and practical tools for amplifying the commercial application of plasma.