Phthalate esters (PAEs) are a widespread environmental pollutant, and their ecological and environmental health risks have gradually attracted attention. To reveal the toxicity characteristics of these compounds, ten PAEs were selected as research objects to establish a cell model. CCK-8 was used to determine cell viability, Western blots were used to determine the content of Nrf₂ in HepG2, and the LD₅₀ collected for the 13 PAEs administered to rats. On this basis, 3D-QSAR models of IC₅₀, LD₅₀ and Nrf2 were established. The experimental results showed that as the time of PAEs exposure increased (24, 48 and 72 h), cell viability gradually decreased. The test concentration (62.5 /125/250 μM) of PAEs exposed for 48 h could significantly increase the content of Nrf2, and the 1000 μM PAEs could inhibit the content of Nrf2. The model is relatively stable and predicts well that the introduction of large and hydrophobic groups may significantly affect the toxic effects of PAEs on cells. The present study provided a potential tool for predicting the LD50 and Nrf2 of new PAEs, and provide a reference for the design of new less toxic PAEs in the future.