In this study, we aimed to improve understanding of the clinical manifestations, laboratory findings, and risk factors of Clostridium perfringens sepsis in patients with acute leukemia and to analyze treatment strategies for improving prognosis. We analyzed clinical manifestations, laboratory data, diagnosis, and treatment strategies in three cases of C. perfringens sepsis in patients with acute leukemia. We also reviewed and analyzed the relevant literature, incorporating our findings into the discussion. All three patients developed septic shock with neutropenia following chemotherapy. Analysis of blood samples confirmed the presence of C. perfringens, and two patients had fulminant intravascular hemolysis and developed multiple organ dysfunction syndrome. Two patients survived and one died despite timely and full-dose antibacterial treatments, blood purification, and noninvasive positive pressure ventilation. Overall, our findings showed that C. perfringens sepsis is rare in patients with acute leukemia but progresses rapidly. A high mortality rate was observed, and patients often experienced refractory shock and intravascular hemolysis. This demonstrates the importance of early detection and diagnosis. Multimodal treatments, including fluid resuscitation, antibiotics, organ support, and blood purification, are essential for success.