Streptococcus pneumoniae (S. pneumoniae) is a human pathogen that causes several important and life-threatening invasive diseases such as pneumonia and meningitis with high morbidity and mortality throughout the world. After transmission to the host, S. pneumoniae is first confronted by the host’s innate immune system before adaptive immune system activation. In the bloodstream, S. pneumoniae is specifically confronted by the complement system, which is a critical part of innate immunity. Complement system participates in host defenses including direct killing of bacteria through the assembly of a membrane attack complex, facilitation of phagocytosis through bacterial opsonization, recruitment and activation of immune cells, vasodilatation and increasing vascular permeability. Unfortunately, S. pneumoniae has developed several strategies to overcome innate and adaptive immune defenses in the respiratory tract. Extending our knowledge of the host immune response to S. pneumoniae is paramount for our improvement of pneumococcal disease diagnosis and treatment of patients. In this review, we outline the immune response developed during S. pneumoniae infection and the strategies developed to overcome host response with a focus on the complement system against S. pneumoniae.