Objective Early growth response-1 (EGR-1), one of immediate early response genes, is involved in diverse cellular response. We recently reported that quercetin increased catalytic subunit of γ-glutamylcysteine ligase (GCLC) via the interaction of EGR-1 to GCLC promoter in INS-1 beta-cells. Therefore, this study investigated molecular mechanisms of quercetin-induced EGR-1 expression and the role of EGR-1 in cell proliferation in INS-1 cells. Methods The expression of EGR-1 protein was detected by Western blot analysis. Additionally, EGR-1 mRNA expression and EGR-1 promoter activity were observed by Northern blot analysis and luciferase assay, respectively. Knock-down of PKA and p38 MAPK was verified by real-time PCR. To examine the transcriptional regulation of EGR-1 by SRE sites, we assessed by EMSA and mutagenesis. Results Quercetin significantly induced EGR-1 protein and its mRNA expressions. This induction of EGR-1 was completely blocked by pretreatment with a PKA inhibitor, H-89 and partially blocked by a p38 inhibitor, SB203580. Additionally, the siRNA-mediated inhibition of PKA and p38 resulted in significant reduction of quercetin-induced EGR-1 promoter activity. Study using truncated EGR-1 promoter constructs showed that serum response element (SRE) sites, not cAMP response element site, were essential for EGR-1 transcription. However, electrophoretic mobility shift assay showed that quercetin did not affect the band intensity of DNA-protein complex on SRE site of EGR-1 promoter. Also, immune-shift assay using serum response factor (SRF) and phospho-SRF antibodies showed no difference between control and quercetin-treated groups. Meanwhile, quercetin significantly increased cell proliferation rate and the overexpression of EGR-1 increased the expression of cyclin D1, a key regulator of G1 to S phase progression. Conclusion Collectively, quercetin-induced EGR-1 expression is largely dependent on PKA and partly on p38 MAPK pathway, and SRE sites of EGR-1 promoter are involved in EGR-1 transcriptional activity, and quercetin may promote cell proliferation via the increase in EGR-1 and cyclin D1 expressions.