We established a model of chronic portal vein catheterization in an awake nonhuman primate to provide a comprehensive evaluation of the metabolic response to low-carbohydrate/high-fat (LCHF; 20% carbohydrate and 65% fat) and high-carbohydrate/low-fat (HCLF; 65% carbohydrate and 20% fat) meal ingestion. Each meal was given 1 wk apart to five young adult (7.8 ± 1.3 yr old) male baboons. A [U-¹³C]glucose tracer was added to the meal, and a [6,6-²H₂]glucose tracer was infused systemically to assess glucose kinetics. Plasma areas under the curve (AUCs) of glucose, insulin, and C-peptide in the femoral artery and of glucose and insulin in the portal vein were higher (P ≤ 0.05) after ingestion of the HCLF compared with the LCHF meal. Compared with the LCHF meal, the rate of appearance of ingested glucose into the portal vein and the systemic circulation was greater after the HCLF meal (P < 0.05). Endogenous glucose production decreased by ∼40% after ingestion of the HCLF meal but was not affected by the LCHF meal (P < 0.05). Portal vein blood flow increased (P < 0.001) to a similar extent after consumption of either meal. In conclusion, a LCHF diet causes minimal changes in the rate of glucose appearance in both portal and systemic circulations, does not affect the rate of endogenous glucose production, and causes minimal stimulation of C-peptide and insulin. These observations demonstrate that LCHF diets cause minimal perturbations in glucose homeostasis and pancreatic β-cell activity.