Summary Eight calves (males, Black and White crossbred with Holstein‐Fresian) were fed milk and milk replacer without (control group) or with potassium orotate (3 mmol./l.) supplementation for 6 weeks after birth. Orotate depressed the biosynthesis of polyamines in mucosa of the gastrointestinal tract (rumen, omasum, abomasum, colon) by decreasing of ornithine decarboxylase activity with a simultaneous compensatory increase of S‐adenosyl‐methionine decarboxylase activity. A lower concentration of spermidine and spermine in the mucosa of the colon was also noted. The above changes were accompanied by increased urinary excretion of ornithine and arginine. Calf adaptation to a high OA intake was associated with an increased activity of the OA metabolizing enzyme complex (orotate phosphoribosyl transferase and orotidine monophosphate decarboxylase) in the liver, while urinary OA losses diminished with age. Increased concentrations of uracil and uridine in the liver and higher urinary excretion of pseudouridine in OA‐fed calves was also observed. Stimulation of pyrimidine metabolism by OA depressed purine synthesis, which was reflected by a decrease of urate, hypoxanthine, and xanthine concentration in the liver. Interestingly OA enhanced urate excretion by the kidneys. OA strongly affected lipid metabolism in calves because total cholesterol, LDL‐, and HDL‐cholesterol, and triglycerides in blood plasma decreased while triglycerides accumulated in the liver of OA‐fed calves. Milk OA in concentrations characteristic of cows with hereditary orotic aciduria exerts an unfavourable effect on the metabolism of polyamines, purines, and lipids in calf tissues.