Patients with liver cirrhosis show hyperammonemia and peripheral inflammation and may show hepatic encephalopathy with cognitive impairment, reproduced by rats with chronic hyperammonemia. Peripheral inflammation induces neuroinflammation in hippocampus of hyperammonemic rats, altering neurotransmission and leading to cognitive impairment. Extracellular vesicles (EVs) may transmit pathological effects from the periphery to the brain. The aims were to assess whether EVs from plasma of hyperammonemic rats (HA-EVs) induce cognitive impairment and to identify the underlying mechanisms.HA-EVs were injected into control rats to study cognitive function and neuroinflammation in hippocampus. We used hippocampal slices from control rats in ex vivo studies to investigate the mechanisms by which extracellular vesicles from hyperammonemic rats induce neuroinflammation and alter neurotransmission.Injection of HA-EVs impaired learning and memory, induced glia activation and increased TNFα and IL-1β in hippocampus. Ex vivo experiments reproduced these proinflammatory alterations which do not occur if TNFα is blocked. HA-EVs increased membrane expression of TNFR1, reduced membrane expression of TGFβR2 and Smad7 and IκBα levels and increased IκBα phosphorylation. This led to increased activation of NF-κB and IL-1β production, altering membrane expression of AMPA and NMDA receptors (NR2B, GluA1 and GluA2 subunits), which would be responsible for cognitive impairment. All these effects of HA-EVs were prevented by blocking TNFα, indicating that they were mediated by enhanced activation of TNFR1 by TNFα.Plasma EVs transmit peripheral alterations to the brain in hyperammonemia and hepatic encephalopathy, inducing neuroinflammation and altering neurotransmission in the hippocampus, which in turn is responsible for cognitive deficits.