The periparturient period poses metabolic challenges for dairy cows resulting in negative energy balance often followed by fatty liver disease, a typical periparturient metabolic disorder, and further health problems. Quercetin (Q), a polyphenolic compound found in plants, has hepatoprotective and antioxidative potential, and can reduce hepatic lipid accumulation in rodents. In ruminants, knowledge on metabolic effects of Q is scarce. Thus, we investigated whether Q affects lipid metabolism, oxidative stress defense, and has hepatoprotective effects in periparturient dairy cows. Because Q is degraded in rumen, 5 cows were given 100 mg Q dihydrate per kg BW daily in 0.9% NaCl solution into a duodenal fistula while control (CTR; n = 5) cows received NaCl only, starting 3 wk antepartum (ap) to 3 wk postpartum (pp). Twice-weekly blood samples were collected and liver was biopsied twice ap and once pp. Selected hepatic transcript abundances were determined by quantitative real-time PCR. Effects of Q were analyzed using repeated-measure ANOVA (SAS PROC MIXED). Duodenal supplementation of Q resulted in higher (P < 0.05) plasma flavonoid levels in Q than in CTR cows. In Q cows pp plasma values of aspartate aminotransferase (AST) were lower (P < 0.05) whereas glutamate dehydrogenase (GLDH) and BHBA levels tended to be lower (P = 0.1). Liver fat content tended (P = 0.1) to be lower in Q cows pp, although groups did not differ (P = 0.7) in fat mobilization indicated by plasma NEFA. We could not show group differences of hepatic mRNA abundance of genes related to lipid metabolism and oxidative stress defense (fatty acid synthase, carnitine palmityltransferase 1A, peroxisome proliferator-activated receptors α and γ, paraoxonase, superoxide dismutase, catalase and glutathione peroxidase). In conclusion, when Q is systemically available during the peripartal period there is potential that metabolic stress and liver damage in dairy cows can be reduced. However, these results should be verified in a larger number of cows and mechanisms of action of Q in cows need to be clarified. Eventually a rumen-protected form of Q has to be developed.