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Objective: To explore etiology, optimize the search direction of etiology, and short-term efficacy evaluation of acute liver failure in children. Methods: Children with acute liver failure who were diagnosed in the First Affiliated Hospital of Zhengzhou University from November 2011 to November 2019 were collected. Gender difference, age, living environment, etiological factors on the seasonal onset and different etiological profile of short-term prognosis were statistically analyzed. Chi-square test or Fisher's exact probability method was used to compare the rate and the constituent ratio between groups. Results: Among the 236 cases, 114 (48.31%) had unknown etiology and 122 (51.69%) had definite etiology. In the definite etiology group, 38 (16.10%), 27 (11.44%), 22 (9.32%), 15 (6.36%), 17 (7.20%), and 3 (1.27%) cases were related to drugs/toxicants, infection, congenital/vascular/biliary diseases, genetic metabolic diseases, tumor-related, and autoimmune diseases. In addition, the overall etiological distribution did not change statistically with factors such as gender, age, and seasonal onset ( P > 0.05), while the difference in different living environments was statistically significant ( P < 0.05). Different initial-diagnosed departments had different etiological rates, with liver transplantation department being the highest (78.26%), and pediatrics department the lowest (26.09%). In 122 children with definite etiology, there was no significant difference in gender ratio between the different etiology groups (P>0.05), but there were significant differences in age, living environment and seasonal onset ( P < 0.05). Among them, congenital development/vascular/biliary tract and infectivity were the main factors in children < 3 years old, and drug/toxin-related factors were the main factors in children > 3 years old. Most of the rural children had drug/toxin and infection-related etiology, while most of the urban children had tumor and drug/toxin-related etiology. In summer and autumn, drug/toxicant correlation was dominant, while in winter and spring, infection correlation was dominant. In the unknown etiology group, the clinical cure + improvement rate between the medical treatment group and the surgical treatment group was not statistically significant (37.50% vs. 20.00%, P > 0.05), while in the definite etiology group, the above differences were statistically significant (43.96% vs. 83.87%, P < 0.05). Among the different etiology groups, the congenital/vascular/biliary group had the best short-term efficacy (72.72%, 16/22), followed by the drug/toxicity-related group (60.53%, 23/38), and the tumor-related group had the worst (23.53%, 4/17). Conclusion: The definite etiology of acute liver failure in about half of children is still vague. The population distribution of children with definite etiology is related to age, living environment and season, but not to gender. However, the different ages, different living environments, and different seasonal onsets have definite etiology, and the short-term clinical efficacy of the treatment is significantly improved after the definite etiology is identified.