The fetus responds to decreases in arterial partial pressure of oxygen by redirecting the blood flow mainly to the brain and the heart, at a cost to other peripheral organs like the kidneys. Renal hypoxia and ischemia stimulate inflammatory and apoptotic responses. Ketamine, an NMDA receptor antagonist, is able to reduce renal immune and inflammatory gene expressions stimulated by hypoxia. Ketamine may have therapeutic potential for protection against ischemic renal damage in fetuses subjected to acute hypoxia. Abstract Acute fetal hypoxia is a form of fetal stress that stimulates renal vasoconstriction and ischemia as a consequence of the physiological redistribution of combined ventricular output. Because of the potential ischemia/reperfusion injury to the kidney, we hypothesized that it would respond to hypoxia with an increase in the expression of inflammatory genes, and that ketamine (an N‐Methyl‐D‐aspartate receptor antagonist) would reduce or block this response. Hypoxia was induced for 30 min in chronically catheterized fetal sheep (125 ± 3 d), with or without ketamine (3 mg kg‐1) administered intravenously to the fetus 10 min prior to hypoxia. Gene expression in fetal kidney cortex collected 24 hr after the onset of hypoxia was analyzed using ovine Agilent 15.5 k array and validated with qPCR and immunohistochemistry in four groups of ewes: normoxic control, normoxia+ketamine, hypoxic control and hypoxia+ketamine (n = 3‐4/group). Significant differences in gene expression between groups were determined with t‐statistics using the limma package for R (P ≤ 0.05). Enriched biological processes for the 427 upregulated genes were immune and inflammatory responses and for the 946 downregulated genes were metabolic processes. Ketamine countered the effects of hypoxia on upregulated immune/inflammatory responses as well as the downregulated metabolic responses. We conclude that our transcriptomics modeling predicts that hypoxia activates inflammatory pathways and reduces metabolism in the fetal kidney cortex, and ketamine blocks or ameliorates this response. The results suggest that ketamine may have therapeutic potential for protection from ischemic renal damage. This article is protected by copyright. All rights reserved