Streptococcus suis serotype 2 (SS2) is a porcine and human pathogen with adhesive and invasive properties. As traditional inactive vaccine has obvious shortcomings, to identify protective antigens would undoubtedly contribute to the development of novel vaccines. HP0197 has been identified as immunogenic protein in the previous study but its protective efficacy was not clear. In the present study, the purified recombinant HP0197 protein could elicit a significant humoral antibody response and could confer significant protection against challenge with lethal dose of SS2 in mice and pigs. In addition, the hyperimmune sera against HP0197 could efficiently kill the bacteria in the opsonized phagocytosis test and conferred significant protection against SS2 infection in the experiment of passive immunization. The present study suggests with strong evidence that the identified protective antigen would be a novel and an effective vaccine candidate for SS2.