Hepatitis E virus (HEV) is one of the major etiologies for acute liver failure. This multicenter retrospective cohort study aimed to investigate the associations of lipid profiles with the risk of HEV‐related acute liver failure (HEV‐ALF) among hospitalized patients with acute hepatitis E. A total of 1061 participants were obtained from three tertiary medical centers in Jiangsu, China, between February 2018 and May 2024. Univariate and multivariate Cox regression models were constructed to assess the associations between lipid profiles and the risk of HEV‐ALF onset. The time‐dependent area under the receiver‐operating‐characteristic curve (AUROC) and decision curve analysis were used to further evaluate the predictive value of blood lipids. After adjusting for potential confounders, total cholesterol (HR = 0.535, 95% CI: 0.437–0.656, p < 0.001), high‐density lipoprotein‐cholesterol (HR = 0.065, 95% CI: 0.027–0.154, p < 0.001), low‐density lipoprotein‐cholesterol (HR = 0.653, 95% CI: 0.512–0.833, p = 0.001), and apolipoprotein A (ApoA) (HR = 0.006, 95% CI: 0.002–0.020, p < 0.001) were significantly associated with a reduced risk of HEV‐ALF. Moreover, blood ApoA exhibited excellent discrimination ability and net benefit for predicting 7‐day (AUROC = 82.47%, 95% CI: 77.92–87.02) and 14‐day (AUROC = 78.81%, 95% CI: 74.13–83.49) HEV‐ALF onset. The findings may provide further evidence on the progression of HEV infection and future risk prediction.