Modulating cell endocytosis activity to reduce host susceptibility to virus represents a promising strategy for antiviral drug development. In this study, we reveal that lactate transporter SLC16A3 as a critical host factor for reducing diverse virus invasion. By performing metabolomics, proteomics, and thermal proteome profiling experiment, AP1G1, a pivotal protein involved in cellular endocytosis, was indiscriminately screened as a chaperone of SLC16A3. SLC16A3 decides the membrane enrichment of AP1G1 by protein interaction, thereby influence host susceptibility to diverse virus. This conclusion was further validated in SLC16A3 knocked-down cells, which indicating a broad-spectrum target for anti-virus drug development to recedes virus entry by blocking the interaction between AP1G1 and SLC16A3. This conclusion has been validated with a patent medicine SFJD (Shufengjiedu). SFJD exhibits strong effect in decreasing the susceptibility of host cells to viral infections. Molecularly, SFJD administration results in disrupting the interaction between SLC16A3 and AP1G1 and reduced membrane localization of AP1G1. Consequently, achieves a receded endocytosis activity of host cells on viral particles. This provide evidence for the practicability of SLC16A3-AP1G1 strategy. Taken together, the regulation on the SLC16A3-AP1G1 interaction represents a broad-spectrum and practicable antiviral strategy. This study offers insights into novel approach for inhibiting viral infections through the alteration of host susceptibility and advances the idea for antiviral drug development.