Sepsis is a significant public healthcare problem, affecting millions of people worldwide each year, killing one in four, and increasing in incidence. Thus, advanced therapeutic strategies are required to treat sepsis patients. Curcumin (Cur) is a promising anti-inflammatory agent for various inflammatory disorders. However, the therapeutic efficacy of Cur is limited due to poor aqueous solubility, rapid degradation, and low bioavailability. The aims of this study were to evaluate the therapeutic potential of Cur-loaded solid lipid nanoparticles (Cur-SLNs) for sepsis treatment. A firefly luciferase transgenic mouse was used to monitor real time interleukin 1β (IL-1β) expression in lipopolysaccharide (LPS)-induced sepsis model to examine the protective effect of Cur-SLNs, and to elucidate its underlying molecular mechanisms. Mice (female or male) were intraperitoneally administered with free Cur or Cur-SLNs (30 mg/kg) before the intraperitoneal delivery of LPS (3 mg/kg). Our results indicated that Cur-SLNs can effectively reduced levels of IL-1β expression compared to free Cur, especially at 3 h after LPS injection. Also, Cur-SLNs significantly decreased the expression of serum pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β as compared with free Cur, but augmented anti-inflammatory cytokine IL-10 by ELISA assay. Further, marked alleviation of the sepsis-induced damage to organs, including kidney, liver, and heart was observed with Cur-SLNs treatment as determined by hematoxylin/eosin-staining. Western blot analyses revealed that Cur-SLNs can significantly lower the expression levels of TLR4, TLR2, and TNF-α in lymph node tissues. Meanwhile, it showed suppressions of NF-κB activation and IκBα degradation levels. In conclusion, we suggested that Cur-SLNs may be used as an effective and safe therapeutic agent in treating sepsis in high-risk patient groups.