TNF‐α expression is elevated in a variety of neuropathologies, including multiple sclerosis, cerebral malaria and HIV encephalitis. However, the consequences of such high cerebral TNF‐α expression remain unresolved. Here, using MRI, we demonstrate that a focal intrastriatal injection of TNF‐α causes a significant, acute reduction (15–30%) in cerebral blood volume (CBV), which is dependent on TNF‐α‐type 2 receptor (TNFR2) activation, and can be ameliorated by pre‐treatment with a non‐specific endothelin (ET) receptor antagonist. An acute breakdown of the blood‐cerebrospinal fluid barrier (B‐CSF‐B) and a delayed breakdown of the blood‐brain barrier (BBB) were also observed using contrast‐enhanced MRI. Furthermore, a significant reduction in tissue water diffusion was apparent 24 h after intrastriatal injection of TNF‐α injection, which may indicate compromise of tissue energy metabolism. Prolonged expression of endogenous TNF‐α, achieved through the use of an adenoviral vector expressing TNF‐α cDNA (Ad5TNF‐α_m), caused a sustained depression in CBV in accordance with the single TNF‐α bolus data. These findings identify vasoconstriction, disrupted tissue homeostasis and damage to the BBBs as adverse effects of TNF‐α within the brain, and suggest that antagonists of the endothelin and TNF‐α type 2 receptors may be therapeutic in TNF‐α‐associated neuropathologies.