The abuse of immunosuppressants causes damage to the immune system, while the pathological proliferation and translocation of symbiotic Candida albicans can result in abdominal infection in immunocompromised people. In this study, we established a mouse peritoneal C. albicans infection model and investigated the effects of preventive application of Sodium New Houttuyfonate (SNH) by analyzing the proportion of immune cells, polarization of peritoneal macrophages, changes in fungal tissue load, and histology, and the data showed prophylactic SNH administration yields a double anti-infection effect in phagocytosis and regulation of immunity according to the immune inflammatory states of the body. In vitro, neutral red, colony counting, cytometric bead array, RT-qPCR, western blot, inhibitor treatment, and detection of reactive oxygen species (ROS) and nitric oxide (NO) production on RAW264.7 macrophages showed SNH can stimulate the production of tumor necrosis factor-alpha (TNF-α) and CC motif ligand 2 (CCL2) and the release of ROS and NO through a TLR2/p38/NF-κB pathway. Taken together, our data provide an innovative insight into the prevention use of exogenous SNH for the treatment of C. albicans infection.