This study examined whether astaxanthin (ASX) could alleviate hepatic steatosis in rats fed a high-fat diet (HFD) by modulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/miR-21 axis. Rats (n = 8/group) were fed either a standard diet (3.8 kcal/g; 10% fat) or HFD (4.6 kcal/g; 40% fat) and treated orally with either the vehicle or ASX (6 mg/kg) daily for 8 days. Another group was fed HFD and treated with ASX and brusatol (an Nrf2 inhibitor) (2 mg/kg/twice per week/i.p.). ASX prevented the gain in body and liver weights and attenuated hepatic lipid accumulation in HFD-fed rats. In the control and HFD-fed rats, ASX did not affect food intake, serum free fatty acid (FFA) content, and glucose and insulin levels and tolerance. However, serum triglyceride (TG), cholesterol, and low-density lipoprotein-cholesterol levels; hepatic levels of TGs and FFAs; and hepatic levels of Srebp1, Srebp2, HMGCR, and fatty acid synthase mRNAs and miR-21 were reduced and the mRNA levels of Pparα were significantly increased in both the groups. These effects were associated with a reduction in the hepatic levels of reactive oxygen species, malondialdehyde, tumor necrosis factor-α, and interlukin-6 as well as an increase in superoxide dismutase levels, total glutathione content, and nuclear levels and activity of Nrf2. miR-21 levels were strongly correlated with the nuclear activity of Nrf2. Brusatol completely reversed the effects of ASX. In conclusion, ASX prevents hepatic steatosis mainly by transactivating Nrf2 and is associated with the suppression of miR-21 and Srebp1/2 and upregulation of Pparα expression.