Aims Suilysin (SLY), a crucial virulence-related factor, has multiple cytotoxicities that are regarded as playing a key role in several diseases induced by Streptococcus suis. The aim of this study was to identify an effective inhibitor of SLY and to evaluate the potential inhibitory effect of the inhibitor against S. suis virulence. Methods and Results Antibacterial activity experiments and haemolysis tests were used to identify the SLY inhibitor ginkgetin, and Western blot analysis and oligomerization inhibition tests were employed to determine the potential mechanism for its inhibition effect. The potential inhibitory effect of ginkgetin against S. suis virulence was then assessed through a cytotoxicity test and a mouse infection model. In this study, we demonstrated that the natural ingredient ginkgetin can significantly reduce the haemolytic activity of SLY to protect against S. suis-mediated cell injury in vitro by directly binding to SLY to block the oligomerization of the protein and reducing the bacterial burden in vivo. Conclusions The results suggest that ginkgetin can start being used as a potential lead drug for the treatment of S. suis infections. Significance and Impact of the Study The prevention and treatment of S. suis infection might be possible through the targeting of SLY by ginkgetin.