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Single Garlic Oil (SGO) extract contains organosulfur compounds such as S-allyl-L-cysteine sulfoxides (alliin), allicin, Z-ajoene, and E-ajoene. This study aimed to observe organosulfur compounds in SGO extract as medicinal plant to decrease inflammatory signaling caused by high fat diet (HFD) consumption. Twenty-four adult males of Balb C mice were divided into six groups: normal diet, HFD treated with statin 26 mg/kgBW, HFD without treatment, HFD treated with SGO 12.5 mg/kgBW, HFD treated with SGO 25 mg/kgBW, and HFD treated with SGO 50 mg/kgBW. Indicators of inflammatory status in the study were liver weight, liver morphology, spleen weight, level of superoxide dismutase (SOD), level of tumor necrosis factor α (TNF-α) in serum, and expression of TNF-α in aorta. Liver weight and spleen weight in SGO treatment group showed a significant decrease compared to HFD without treatment group (P < 0.05). SGO also showed that it could reduce hepatic steatosis compared to HFD without treatment group on hepatic tissue of mice. The level of SOD was significantly increased in SGO treatment group compared to HFD without treatment group (P < 0.05). SGO has the ability to increase antioxidant activity of SOD resulted in the reduced of the level of inflammatory cytokine TNF-α in serum and expression of TNF-α in aorta, the reduced of the liver and spleen weight and the improvement of hepatic steatosis. These results indicated that SGO can be well considered as an alternative treatment to decrease inflammatory signaling caused by HFD.