Grass carp reovirus (GCRV) is one of the main pathogens harmful to the health of Ctenopharyngodon idella, causing severe grass carp hemorrhagic disease. To explore the difference between naturally and artificially injection infected C. idella with GCRV-II virus in clinical symptoms, pathological features, and virus distribution, we used clinical necropsy, histopathological observation, molecular biology detection, real-time fluorescent quantitative (qRT-PCR), and Western blot detection methods for experiments. We compared the clinical symptoms of naturally diseased and artificially injected C. idella, and found that the eye socket, operculum, mouth cavity, abdomen, fin base, intestine and muscle of the diseased C. idella showed obvious punctate hemorrhage. The bleeding of the latter was more serious than that of the former. Compared with histopathological sections, it was found that the infected tissues had different degrees of congestion and erythrocytes accumulation. Among them, the intestines, muscles and hepatopancreas of the artificial injection of C. idella were more severely affected, showing more serious intra-tissue bleeding and lesions. The gills and spleen of naturally diseased C. idella were more severely affected, the gills showed more serious hyperaemia and inflammatory hyperplasia, and large areas of hemosiderin agglutination lesions appeared in the spleen. The results of qRT-PCR and Western blot tests showed that GCRV was distributed in different tissues. The head kidney had a relatively high viral load in diseased fish by the two infection methods. The viral load of the hepatopancreas, intestine, and muscle was higher in artificially injection infected fish. The amount of virus is higher in the trunk kidney, gill, and spleen in naturally diseased fish. Therefore, the hepatopancreas, intestine, and muscle may be the main target organs of GCRV invasion in artificial injection infection, while the gill may be the main target organ of GCRV invasion in the case of natural disease, and the target organ for virus accumulation is the head kidney. The head kidney is the "virus library" of GCRV. This study is helpful to deeply analyze the pathogenesis of GCRV and the immune responses of C. idella, and may provide references for the prevention and treatment of C. idella hemorrhagic disease and the development of the vaccine.