In this study, the protective effect of heat-transformed saponins of American ginseng (HTS) on mice infected with listeria monocytogenes (Lm) was investigated. Mice in the HTS group and American ginseng leaf-stem saponins (AGS) group were infected with Lm after 14 days of continuous intervention. After the infection, gavage was continued for another 7 days, to examine the protective effect of HTS on infected mice. In vitro antibacterial experiments showed that HTS had a significant antibacterial effect, with an inhibition zone diameter of 18.47 mm. The liver and spleen coefficients of the HTS pretreatment group (0.0593 and 0.00433, respectively) and the negative group (0.0518 and 0.00678, respectively) were statistically different (p<0.05). The kidney coefficients between the HTS pretreatment group (0.0155) and blank group (0.0155) was statistically different (p<0.1). Compared with the blank group, the liver color of the negative group was abnormal, and the liver section showed obvious inflammatory cell infiltration, loss of nuclei and hypertrophy. The color and texture of the liver of the HTS pretreatment group were normal, with no obvious pathological changes. The numbers of white blood cell (WBC) and neutrophil (NEUT) of the HTS pretreatment group (5.62 and 2.19, respectively) were smaller than those of the negative group (6.13 and 2.40, respectively). The levels of IL-1β and IFN-γ in the liver of the HTS pretreatment group (76.75 pg/mg and 74.67 pg/mg, respectively) were significantly lower than those of the negative group (115.14 pg/mg and 335.45 pg/mg, respectively), with the differences being statistically significant (p<0.05). Therefore, HTS can reduce the damage of infected mice by reducing the secretion of inflammatory cells, alleviating pathological forms such as inflammatory cell infiltration in the liver tissue, and reducing the release of inflammatory cytokines, thereby exerting a protective effect on the liver of infected mice.