Hypothalamic inflammation was recently found to mediate obesity-related hypertension, but the responsible upstream mediators remain unexplored. In this study, we show that dietary obesity is associated with extracellular release of mitochondrial DNA (mtDNA) into the cerebrospinal fluid, and that central delivery of mtDNA mimics TGFβ excess to activate downstream signaling pathways. Physiological study reveals that central administration of mtDNA or TGFβ are both sufficient to cause hypertension in mice. Knockout of the TGFβ receptor in pro-opiomelanocortin neurons counteracts the hypertensive effect of not only TGFβ but mtDNA excess, while the hypertensive action of central mtDNA can be blocked pharmacologically by a TGFβ receptor antagonist or genetically by TGFβ receptor knockout. Finally, we confirm that obesity-induced hypertension can be reversed through central treatment with TGFβ receptor antagonist. In conclusion, circulating mtDNA in the brain employs neural TGFβ pathway to mediate a central inflammatory mechanism of obesity-related hypertension.