Clostridium perfringens (C. perfringens) is a gram-positive anaerobic bacillus. As an opportunistic pathogen, C. perfringens can colonize the intestine of infants, but highly pathogenic forms are uncommon in newborns. Sporadic cases of neonatal infection have been reported worldwide, but no case has yet been reported in Chinese neonates. We herein report the first Chinese neonate who developed severe intravascular hemolysis and necrotizing enterocolitis following C. perfringens septicemia. A 7-day-old full-term female newborn was admitted to our hospital with necrotizing enterocolitis. The patient developed severe intravascular hemolysis on the day of admission and underwent continuous renal replacement therapy for hyperkalemia and severe acute kidney injury. Despite optimal treatment, this baby died at 20 hours after admission. Clinical metagenomic next-generation sequencing for pathogen detection showed a positive result for C. perfringens. Literature on C. perfringens-associated sepsis in neonates was reviewed to offer a reference for clinical practice. Our case demonstrates that neonatologists should consider a diagnosis of C. perfringens infection in a newborn when symptoms of severe intestinal infection and intravascular hemolysis are present, so that early treatment can be initiated.