Therapy to enhance host immune defenses may improve outcomes in serious infections, especially for antibiotic-resistant pathogens. Recombinant human plasma gelsolin (rhu-pGSN), a normally circulating protein, has beneficial effects in diverse preclinical models of inflammation and injury. We evaluated delayed therapy (24–48 hours after challenge) with rhu-pGSN in a mouse model of pneumococcal pneumonia. rhu-pGSN without antibiotics increased survival and reduced morbidity and weight loss after infection with either penicillin-susceptible or penicillin-resistant pneumococci (serotypes 3 and 14, respectively). rhu-pGSN improves outcomes in a highly lethal pneumococcal pneumonia model when given after a clinically relevant delay, even in the setting of antimicrobial resistance.