Objective To analyze the components of Lonicerae japonicae flos ( the dried flower bud or newly bloomed flower of Lonicerae japonicae Thunb. ) water extract (LJFWE) and its potential mechanism on improving sepsis, and to verify its effects on sepsis in vitro using RAW 264. 7 murine macrophages cells. Methods (1) UPLC-QE Orbitrap MS was used to identify LJFWE compounds and search for the target genes on improving sepsis. (2)The multiple disease databases were used to build a sepsis target database. (3) RT-PCR was used to verify the core genes adjusted by LJFWE in sepsis, after the establishment of the RAW 264. 7 cell sepsis model. Results 23 active components on improving sepsis were obtained under the UPLC-QE Orbitrap MS in positive and negative ion modes with comparing the local database and literature, including Luteolin, kaempferol, quercetin, loganin and caffeic acid in LJFWE. MAPK8、TP53、RELA、 MAPK1 and MYC were predicted as the key targets. RT-qPCR results showed that LJFWE down-regulated the expression of inflammation-related factors ( IL-1β, IL-6, IL-10, iNOS, TNF-α) and five key target genes (MAPK8, TP53, RELA, MAPK1, MYC) compared with the model group. Conclusions Luteolin, kaempferol, quercetin, loganin, and caffeic acid may be the effective ingredients in the treatment of sepsis in LJFWE. MAPK8,TP53,RELA,MAPK1 and MYC and inflammation-related factors ( IL-1β, IL-6, IL-10, iNOS,TNF-α) may be the key targets of LJFWE in the treatment of sepsis. This study provided a theoretical basis for further verification of the mechanism of Lonicerae japonicae flos in the treatment of sepsis.