This report aims to deepen the understanding of the pathogenesis, diagnosis, clinical characteristics, and treatment of overwhelming postsplenectomy infection (OPSI). A patient treated at Taihe Hospital for tuberculous OPSI is described, and relevant literature is reviewed. Broad-spectrum antibiotics, suppression of the systemic inflammatory reaction, and anti-shock measures were the keys to the successful treatment of this condition. OPSI is a life-threatening condition and has a high mortality rate. Early diagnosis, use of anti-inflammatory glucocorticoids, and administration of high-dose gamma globulin and ulinastatin for the treatment of OPSI may improve outcomes.