We have previously reported that overexpression of 14-3-3ε is correlated with high risk of extrahepatic metastasis and worse survival in hepatocellular carcinoma (HCC). Early growth response protein 1 (EGR1) is a transcriptional regulator which contributes to modulating cell proliferation and differentiation. However, whether EGR1 modulates HCC progression has not yet been elucidated. In this study, we found that EGR1 is a potential downstream regulator of 14-3-3ε. Both of transient and stable overexpression of 14-3-3ε significantly induced EGR1 expression which was determined by Western blotting and real-time PCR analysis. Furthermore, we found that EGR1 was involved in 14-3-3ε-promoted HCC progression through activation of MEK/ERK pathway. Moreover, we found that sorafenib attenuated 14-3-3ε-induced EGR1 expression. These results suggest that EGR1 plays as a crucial factor that contributes in 14-3-3ε-promoted HCC tumor progression.