OBJECTIVE To compare the acute toxicity characteristics and differences of water extracts from unprocessed and different processed products of Psoraleae Fructus in mice. METHODS Kunming mice were divided into 36 groups, including Psoraleae Fructus raw product group, stir-fried group, salt-baked group, Leigong group, and wine soaked group, as well as control group. Each group of mice was given a single intragastric administration of 0.04 mL·g-1 and observed for 14 d. The body weight, serum biochemical indices, and mortality of the mice were detected, and the LD50 value was calculated to study the toxicity differences of Psoraleae Fructus raw product and different processed products. RESULTS There was no statistically significant difference in the body weight of mice before administration in different groups. On the first day of administration, some mice in the administration group showed a certain decrease in body weight. The LD50 values of the Psoraleae Fructus raw product group, stir-fried group, salt-baked group, Leigong group, and wine soaked group were 63.20, 56.92, 51.95, 88.61, 59.02 g·kg-1, respectively. Compared with the control group, the serum ALT and TBA levels in the male mice in the Psoraleae Fructus raw product group were significantly increased; the serum ALT, AST, and TBA levels in the stir-fried group were significantly increased, but the ALP level was not statistically significant; the serum ALP, ALT, AST, and TBA levels in the salt-baked group, Leigong group, and wine soaked group were significantly increased. Compared with the control group, the serum ALP, ALT, AST, and TBA levels in female mice in the Psoraleae Fructus raw product group, salt-baked group, Leigong group, and wine soaked group were significantly increased; the serum ALT, AST, and TBA levels in the stir-fried group were significantly increased; all groups had significantly decreased TP levels. Pathological results showed that there was no abnormality in the liver of mice in the control group; the liver of mice in the Psoraleae Fructus raw product group, stir-fried group, salt-baked group, Leigong group, and wine soaked group had pathological changes such as vacuolar degeneration of liver cells, glycogen degeneration of liver cells, loose cytoplasm of liver cells, and partial central hepatocellular hypertrophy; the degree of liver damage in mice caused by different processed products compared with the raw product group: raw product group > wine soaked group > stir-fried group > salt-baked group > Leigong group. Among them, the wine soaking method caused the highest degree of liver damage, while the Leigong method caused the least. CONCLUSION Psoraleae Fructus has different toxicities after being processed by different methods. According to LD50, the toxicity of Leigong method processed products is significantly reduced.