Invasive pneumococcal diseases incur significant mortality, morbidity and economic costs. The most effective strategy currently available to reduce the burden of these diseases is vaccination. In this study, we evaluated the protective efficacy of immunizing mice with caseinolytic protease (ClpP) protein antigen whose gene sequences were shown to be highly conserved in different strains of Streptococcus pneumoniae in an invasive-disease model (intraperitoneal infection model), and protection against invasive challenge with 12 different serotypes of S. pneumoniae was assessed in two murine strains. Our findings demonstrated that active immunization with ClpP and passive immunization with antibodies specific for ClpP could elicit serotype-independent protection effectively against invasive pneumococcal infection. Therefore, to our knowledge, this study is the first report that immunization with single pneumococcal ClpP protein antigen could protect against such broad-range pneumococal strains, which thus supports the development of ClpP as a human penumococcal vaccine.