Heart failure (HF) patients exhibit a wide range of cognitive and mood abnormalities, especially hippocampus abnormality. Unfortunately, there are few treatments for hippocampus abnormality with HF. Yixinshu (YXS), a traditional Chinese herbal medication, has been found to improve cardiac function in an animal model. However, the effect of treatment with YXS on the hippocampus abnormality induced by heart failure and the related mechanisms remain unclear. In this study, a coronary artery ligation model of HF was treated by the daily intragastric administration of YXS or saline for six weeks. Echocardiography and ELISA for BNP and NT-proBNP were used to determine cardiac function. Western blot assays were used to determine the protein levels of ZO-1, AQP4 and PPARg. We found that YXS significantly improved cardiac function and reduced BNP and NT-proBNP. Meanwhile, YXS also protected the integrity of the blood brain barrier (BBB) and attenuated the inflammation of the hippocampus in rats with HF. Moreover, the reduction of the expression level of PPARg was significant in rats with HF via treatment by YXS. In conclusion, long-term treatment with YXS may protect against heart failure and hippocampus abnormality induced by heart failure via the PPARg pathway.