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<i>Streptococcus suis</i> (<i>S. suis</i>) is a zoonotic pathogen with a global distribution, which causes serious diseases in both humans and animals and economic losses in the swine industry. As antibiotic resistance increases, there is an urgent imperative to explore novel antibacterial alternatives. In the present study, we selected the anticancer drug 5-fluorouracil (5-FU) approved by the Food and Drug Administration (FDA) as a candidate drug to treat <i>S. suis</i> infections. The results showed that various pathogens, especially <i>S. suis</i>, are more sensitive to 5-FU. Moreover, the cytotoxicity of 5-FU is relatively low. Extensive in vitro assays demonstrated the pronounced bacteriostatic and bactericidal efficacy of 5-FU against susceptible and multidrug-resistant <i>S. suis</i> strains. Its mechanisms of action include damage to the bacterial cell walls and membranes, resulting in the leakage of intracellular components, and the inhibition of thymidylate synthase (TS), leading to a depletion of deoxythymidine triphosphate (dTTP) pools, ultimately causing thymine-less death and lethal DNA damage in bacteria. Gene-knockout experiments further showed that 5-FU played a role by inhibiting the <i>thyA</i> gene-encoding thymidine synthase. Finally, we determined that <i>S. suis</i> infections can be alleviated by 5-FU in the mouse infection model. This study emphasizes the antibacterial potential of 5-FU against <i>S. suis</i> and provides evidence for its targeting of bacterial membrane damage and DNA damage. In summary, 5-FU can control <i>S. suis</i> infection and is expected to become a new alternative to antibiotics.