Sepsis and septic shock are life threatening complications and most common cause of death in intensive care units. Thymoquinone, a constituent of nigella sativa (black seed), holds exceptional promise as an anti-cancer and anti-inflammatory agent. No evidence has been published, however, whether this compound has a protective effect from sepsis-related morbidity, mortality and associated organ dysfunction. To examine this, two sets of mice (n=12 per group), with parallel control groups, were acutely treated with thymoquinone intraperitoneal injections of 1.0 and 2.0mg/kg body weight, and were subsequently challenged with endotoxin Gram-negative bacteria (LPS O111:B4). In another set of experiments, thymoquinone was administered at doses of 0.75 and 1.0mg/kg/day for three consecutive days prior to sepsis induction with live Escherichia coli. Survival of various groups was computed, and renal, hepatic and sepsis markers were quantified. Thymoquinone reduced mortality by 80-90% and improved both renal and hepatic biomarker profiles. The concentrations of IL-1? with 0.75 mg/kg thymoquinone dose was 310.8 ? 70.93 and 428.3 ? 71.32 pg/ml in the 1mg/kg group as opposed to controls (1187.0 ? 278.64 pg/ ml; P<0.05). Likewise, IL-10 levels decreased significantly with 0.75 mg/kg thymoquinone treatment compared to controls (2885.0 ? 553.98 vs. 5505.2 ? 333.96 pg/ml; P<0.01). Mice treated with thymoquinone also exhibited relatively lower levels of TNF-? and IL-2 (P values=0.1817 and 0.0851, respectively). This study gives strength to the potential clinical relevance of thymoquinone in sepsis-related morbidity and mortality reduction and suggests that human studies should be performed.