Crocin is the major yellow pigment of saffron and gardenia yellow, which are extracts of Crocus sativus stigmas and Gardenia jasminoides fruits, crocin can prevent chronic stress induced oxidative stress damage in the brain, liver and kidneys, the purpose of this study was to evaluate the protective and anti-inflammatory effect of crocin against L-methionine induced hyperhomocysteinemia and oxidative stress in rats. Thirty male albino rats were divided into three equal groups. Group I (normal group): rats administered distilled water. Group II (L-Methionine induced hyperhomocysteinemia (HHcy): rats received L-methionine (1.7 g/kg b.w) orally daily for continuous 8 weeks. Group III (HHcy + crocin treated group) rats received crocin for 4 weeks after induction of hyperhomocysteinemia inrta peritoneal once per day at a dose of (50 mg/kg body weight/day, I.P). The obtained results showed significant increase in serum homocysteine, lipid profile (cholesterol, triglyceride), liver enzymes (ALT, AST and ALP) activities, liver tissue L-MDA levels and inflammatory markers (TNF-α and IL-8) in hyperhomocysteinemic (HHcy) rats. However, activities of liver tissue antioxidant enzymes SOD and GSH concentration were markedly decreased. Administration of crocin to HHcy rats caused significant improvement of all previous parameters towards its normal ranges. These results suggested that, crocin treatment may have a protective effect against hyperhomocysteinemia induced oxidative stress in rats through free radical scavenging and anti-inflammatory activity as well as regenerating endogenous antioxidant defense system mechanisms.