Sepsis is characterized by excessive inflammatory responses triggered by strong innate immune activation, leading to organ dysfunction. In sepsis, Interleukin-6 (IL-6) levels are markedly elevated, driving pro-inflammatory cascades that cause tissue injury and systemic complications. LMT-28, an oxazolidinone derivative discovered in our laboratory, directly binds to gp130 and inhibits IL-6 activity. It is orally available, non-toxic, and has shown therapeutic efficacy in various inflammatory disease models. This study aimed to investigate whether the LMT-28 could attenuate inflammation and improve survival in the sepsis mouse model. LMT-28 suppressed both classic and trans-signaling of IL-6 in HEK-Blue cells, with greater inhibition efficacy against trans-signaling.  In RAW 264.7 cells, LMT-28 attenuated LPS-induced IL-6 signaling and production of inflammatory mediators. In an LPS-induced septic mouse model, LMT-28 significantly improved survival, reduced serum cytokines and sepsis biochemical markers, and suppressed downstream IL-6 signaling. In the CLP model, LMT-28 reduced IL-6 downstream signaling in lung and liver. Collectively, LMT-28 effectively inhibits IL-6 signaling, improves survival, and mitigates inflammation in mouse sepsis model.