The hepatitis E virus (HEV) causes hepatitis E and is an important human pathogen. We have previously shown that the HEV open reading frame 3 (ORF3) protein promotes survival of the host cell. Here we report finding increased expression of glycolytic pathway enzymes in ORF3-expressing cells. Promoter analysis of these genes revealed the ubiquitous presence of hypoxia inducible factor (HIF) responsive element (HRE). Dominant-negative and siRNA studies showed increased expression of glycolytic pathway genes by the ORF3 to be mediated by the HIF-1 transcription factor. Our results showed that HIF-1α, a highly unstable subunit of the HIF-1, was stabilized in ORF3-expressing cells. This was through phosphatidylinositol-3-kinase (PI3K) mediated activation of Akt/protein kinase B. Enhanced binding to the consensus HRE and increased transactivation activity of HIF-1 were also observed in ORF3-expressing cells. The HIF complex recruits the transcriptional adapter/histone acetyltransferase protein p300/CBP to target gene promoters and p300/CBP phosphorylation is required for this interaction. We show that ORF3-mediated extracellularly regulated kinase (Erk) activation was responsible for the observed increase in phosphorylation and transactivation activity of p300/CBP. Our results reveal a two-pronged strategy through which the ORF3 protein might modulate the energy homeostasis in HEV infected cells and thus contribute to pathogenesis.