BACKGROUND: Whether circulating histones in gut lymph contribute to organ failure and impact of chaiqin chengqi decoction (CQCQD) on histones in severe acute pancreatitis (SAP) remain elusive. PURPOSE: To verify the role of histones in gut lymph of SAP and evaluate the effect of the CQCQD on them. METHODS: Sodium taurocholate was retrogradely infused into pancreatobiliary duct to induce SAP in rodents. Various regimens of CQCQD were administered intragastrically or via duodenum followed by dynamic gut lymph collection in rats. The impact of gut lymph and histones on endothelial cell viability and lymphocytes was determined. Components of CQCQD in gut lymph were identified by UHPLC-MS and their binding activities with histones were quantified by biolayer interferometry followed by validation in vitro and in vivo in mice. RESULTS: The histone level was significantly increased in gut lymph of SAP at various time points assessed, closely correlating with multiple organ injury (MOI) indices and contemporary cell viability. Inhibition of histones reduced cytotoxicity induced by SAP-conditioned gut lymph. CQCQD reduced apoptotic cell death in mesenteric lymph nodes, histone level, and cytotoxicity of gut lymph, alleviating MOI parameters. Baicalin and baicalein were amongst top 13 identified CQCQD components absorbed into gut lymph to actively bind histones, block membrane disruption and calcium influx of lymphocytes, and inhibit their cytotoxicity. Both baicalin and baicalein mitigated histone- and SAP-induced MOI indices in mice. CONCLUSION: Histones are key toxic factors in the gut lymph of SAP and their antagonism by baicalin and baicalein offers a novel therapeutic strategy.