Few studies have evaluated the biomarker changes of fluoride exposure. In order to explore early and sensitive indicators, animal experiment was designed. Ninety-six healthy SD rats (48 males and 48 females) weighing approximately 60 g were randomly divided into six groups of 16 animals each by gender average. Control animals were supplied with distilled water only as group 1. Exposure groups’ animals were treated with 2, 4, 8, 16, and 32 mg NaF/kg bw, respectively, as groups 2, 3, 4, 5, and 6. Our study found that contents of white blood cell (WBC), lymphocyte percentage (LYMPH%), lymphocyte (LYM), mean platelet volume (MPV), and platelet distribution width (PDW) increased significantly in high-fluoride-exposure groups (p?<?0.05), which revealed that immune system may be interfered by high fluoride. Meanwhile, levels of alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), and ALT/AST in groups 5 and 6 decreased significantly compared to those in control group (p?<?0.05), as well as the concentration of uric acid (UA) in groups 3, 4, 5, and 6 exhibited the same trends (p?<?0.05). On the contrary, the level of blood B2 microglobulin (BB2MG) increased significantly (p?<?0.05) in groups 4, 5, and 6. Changes of ALT, AST, UA, and BB2MG suggested the functions of the liver and kidney be altered by fluoride exposure. At the same time, the ATF4 content decreased gradually with the increase of fluoride concentration; furthermore, a highly significant (r?=?-0.586, p?<?0.01) negative relationship between ATF4 content and fluoride exposure level was found. Results meant that clinical indicators cannot act as indicators of high fluoride exposure, and it also suggested that protein ATF4 might be the early and sensitive indicator in epidemiologic study of high fluoride exposure.