This experiment aims to investigate the effect of Siraitia grosvenorii kaempferitrin (SGK) on anti-inflammatory and antioxidant stress abilities in chronic sleep deprivation (CSD) mice. Fifty-six healthy four-week-old male ICR mice were randomly divided into seven groups according to their body mass, including the blank control group, model control group,DMSO control group, positive control group, low-dose, medium-dose and high-dose groups of SGK, with eight mice in each group. Except for the blank control group, the remaining six groups were subjected to eighteen hours every day of sleep deprivation in mice using the modified multiple platforms method for four consecutive weeks. After successful establishing model, mice were gavaged for four weeks. The nuclear factor κB (NF-κB) , tumor necrosis factor-α (TNF-α) and malondialdehyde (MDA) contents, total antioxidant capacity (T-AOC) , the activities of superoxide dismutase (SOD) in the brain and serum of mice were detected by using kit methods. The expression levels of NF-κB, TNF-α, SOD-1 and SOD-2 mRNA in the brain and serum of mice were determined by quantitative real-time PCR (qRT-PCR) . The results showed that SGK significantly increased the T-AOC, SOD activities in the brain and serum of CSD mice, and significantly up-regulated the expression levels of SOD-1 and SOD-2 mRNA (P<0.01) ; SGK significantly reduced the NF-κB, TNF-α and MDA contents in the brain and serum of CSD mice, and significantly down-regulated the expression levels of NF-κB and TNF-α mRNA (P<0.01). In conclusion, SGK can improve the anti-inflammatory and antioxidant stress abilities of CSD mice.