Previously, we have reported that high mobility group box 1 (HMGB1), a proinflammatory mediator in sepsis, is released via the IFN-${eta}$-mediated JAK/STAT pathway. However, detailed mechanisms are still unclear. In this study, we dissected upstream signaling pathways of HMGB1 release using various molecular biology methods. Here, we found that calcium/calmodulin-dependent protein kinase (CaM kinase, CaMK) is involved in HMGB1 release by regulating IFN-${eta}$ production. CaMK inhibitor, STO609, treatment inhibits LPS-induced IFN-${eta}$ production, which is correlated with the phosphorylation of interferon regulatory factor 3 (IRF3). Additionally, we show that CaMK-I plays a major role in IFN-${eta}$ production although other CaMK members also seem to contribute to this event. Furthermore, the CaMK inhibitor treatment reduced IFN-${eta}$ production in a murine endotoxemia. Our results suggest CaMKs contribute to HMGB1 release by enhancing IFN-${eta}$ production in sepsis.