Because gut absorption and liver sequestration are major mechanisms of mineral homeostasis, intestinal and hepatic bypass with parenteral feeding can lead to mineral toxicities. We employed a piglet model with multiple feeding routes to identify target organs susceptible to abnormal accumulation of minerals and to determine the importance of intestinal or hepatic metabolism. Fifteen 2- to 4-day-old piglets were fed identical complete elemental diets continuously for 8 days via central venous (intravenous [IV]), gastric (intragastric [IG]), or portal (intraportal [IP]) catheters. Concentrations of calcium, phosphorus, magnesium, zinc, copper, iron, manganese, sodium, potassium, and chloride were measured in small intestinal mucosa, liver, kidney, and femur. Compared with IG-fed piglets, mineral sequestration patterns in IV- and IP-fed piglets can be attributed to bypass of intestinal absorption inefficiencies, with moderate accumulations of minerals in tissues involved in mineral homeostasis. However, differences between IP and IV feeding were notable for iron, manganese, and copper, suggesting first-pass hepatic metabolism is key to homeostasis of these minerals. Moreover, manganese and copper sequestration patterns reflected that for zinc, suggesting induction of metallothionein by parenteral zinc could interfere with metabolism of other minerals. We conclude that parenteral delivery of minerals to neonates needs to consider not only absorption efficiency but also mineral interactions and potentially toxic accumulation in target tissues, with particular concern for iron, copper, and zinc.