Gentianella acuta (G. acuta) has been widely used as a traditional medicine by Chinese Mongolian populations for the treatment of heart diseases and has also been tested in modern pharmacological experiments. However, the effects of G. acuta on cardiovascular damage and inflammation under conditions of hypercholesterolaemia remain unclear. The present study investigated the effects and mechanisms of the water extract of G. acuta on cardiovascular damage and inflammation caused by a high-cholesterol diet. Male Sprague-Dawley rats were fed a high-cholesterol diet for 4 weeks to establish the hypercholesterolaemia rat model, and they were administered physiological saline or 1.2 g/kg of G. acuta by gavage starting from the 15th day. After the last administration, the blood, heart and thoracic aorta samples were collected and examined. It was revealed that G. acuta treatment could ameliorate cardiomyocyte disorder and thoracic aortic vessel wall damage, reduce serum lipid levels and inflammatory factors and improve heart function. Compared with the Model group, the serum levels of triglycerides, total cholesterol, low-density lipoprotein and tumour necrosis factor-α were decreased, and the high-density lipoprotein and interleukin-10 levels were increased in the Model-G group. Moreover, in both the heart and thoracic aorta, G. acuta reduced the expression and phosphorylation of inhibitor of nuclear factor kappa-B kinase β (IKKβ), inhibitor of NF-κB-α (IκBα) and p-nuclear factor kappa-B (NF-κB). Therefore, G. acuta may exert an inhibitory effect on the IKK/IκB/NF-κB signalling pathway to protect the heart and thoracic aorta in hypercholesterolaemic rats.