Sepsis is an organ dysfunction caused by dysregulation of immune response towards systemic infection with high incidence and mortality rate. Innovative breakthrough is required to manage sepsis especially extended spectrum beta lactamase (ESBL) producing Escherichia coli (E. coli) induced sepsis. Utilization of Piper betle extract to manage sepsis could be considered as an alternative therapy and should be proven scientifically so meropenem utilization could be reduced. This study aimed to evaluate the antimicrobial effect of Piper betle ethanolic extract in BALB/c mice infected with ESBL producing E. coli. We identified terpene, apiol, polyphenol, eugenol, myristicin, flavonoid, safrole, lynalil acetate, and allyl tetramethoxy benzene in the Piper betle ethanolic extract using thin layer chromatography. The minimum inhibitory concentration of the Piper betle ethanolic extract against ESBL producing E. coli was 3 mg/mL assessed using broth dilution method. We evaluated the effect of Piper betle ethanolic extract to the survival rate of BALB/c mice infected with ESBL producing E. coli. The single dose administration of Piper betle ethanolic extract prolonged the survival rate of the infected BALB/c mice for 6 hours.