Abstract This study aimed to explore the effect of Tofacitinib on endothelial dysfunction and cerebral levels of brain‐derived neurotrophic factor (BDNF) in the adjuvant‐induced arthritis (AIA) rat model. Tofacitinib (10 mg/kg twice a day) or vehicle was administered from the first signs of inflammation. Arthritis scores were daily monitored while other parameters including endothelial function assessed from aortic rings, radiographic scores, blood pressure, heart rate, circulating levels of triglycerides, cholesterol, and interleukin (IL)‐1β, tumor necrosis factor‐α (TNF‐α), IL‐17A, and cerebral BDNF levels were determined after 3 weeks of treatment. A group of non‐AIA rats served as controls. In AIA rats, as compared with vehicle, Tofacitinib significantly reduced arthritis and radiographic scores, decreased total cholesterol and low‐density lipoprotein cholesterol (LDL‐C), but changed neither blood pressure nor heart rate and proinflammatory cytokines levels. It also fully restored acetylcholine (Ach)‐induced relaxation ( p < 0.05) through increased nitric oxide (NO) synthase activity, reduced BH 4 deficiency and O 2 −° production, decreased cyclo‐oxygenase‐2 (COX‐2)/arginase activities, and enhanced endothelium‐derived hyperpolarizing factor (EDHF) production. These effects translated into a decrease in atherogenic index and an elevation of BDNF levels in the prefrontal cortex ( p < 0.05) and hippocampus ( p < 0.001). The present study identified Tofacitinib as an efficient therapeutic option to reduce cardiovascular risk and improve BDNF‐dependent cognition in arthritis.