Objective To explore the efficacy of meropenem in the treatment of neonatal carbapenem-resistant Klebsiella pneumoniae (CRKP) sepsis and its influencing factors, so as to provide reference for reasonable use of antibiotics in clinic. Methods A total of 27 neonates who were diagnosed as CRKP sepsis in Shanghai Children's Hospital from Jun. 2014 to Jun. 2018 were included in this retrospective study. The clinical efficacy of meropenem was evaluated and the patients were divided into two groups:meropenem monotherapy effective group and meropenem monotherapy ineffective group who required other antibiotics for combination therapy. The perinatal factors, prior exposure to carbapenems and other clinical characteristics were compared between the two groups. Results The effective rate of meropenem monotherapy in treating neonatal CRKP sepsis was 48.1% (13/27), and the overall effective rate was 74.1% (20/27) when another antibiotic was added. The incidences of open wound after surgery (7/14 vs 1/13), septic shock (7/14 vs 1/13), positive culture of sterile coelomic fluid (6/14 vs 0/13), and invasive mechanical ventilation (10/14 vs 1/13) were higher in meropenem monotherapy ineffective group than in meropenem monotherapy effective group (all P<0.05), and the diameter of CRKP inhibition zone in meropenem monotherapy ineffective group was smaller than that in meropenem monotherapy effective group ([9.14±3.37] mm vs[12.85±5.27] mm, P<0.05). Conclusion Meropenem monotherapy is effective for treatment of neonatal CRKP sepsis. Other antibiotics are recommended when the patients also have open wound after surgery, septic shock, positive culture of sterile coelomic fluid, invasive mechanical ventilation, or smaller inhibition zone of CRKP on meropenem.