Caseinolytic protease (ClpP) has been found to be highly conserved among different strains of Streptococcus pneumoniae and intraperitoneal immunization with ClpP could elicit protection against invasive pneumococcal infections. In this study, mucosal immunization with ClpP antigen induced both systemic and mucosal antibodies, and in this way reduced lung colonization in an invasive pneumococcal pneumonia model and also protected mice against death in an intraperitoneal-sepsis model. Surface localization of ClpP was confirmed using flow cytometry analysis. Furthermore, characterization of human sera for anti-ClpP IgG antibody levels demonstrated that ClpP protein was immunogenic in healthy children and was expressed during disease based on the elevated antibody levels in infected individuals. Finally, we describe that in vitro functional anti-ClpP antibody could kill streptococcus pneumoniae by polymorphonuclear leukocytes in a complement-dependent assay. To our knowledge, this is the first study about the protective efficacy of mucosal immunization with ClpP as a promising pneumococcal protein antigen.