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Hematopoietic regeneration following chemotherapy may be distinct from regeneration following radiation. While we have shown that epidermal growth factor (EGF) accelerates regeneration following radiation, its role following chemotherapy is currently unknown. We sought to identify EGF as a hematopoietic growth factor for chemotherapy‐induced myelosuppression. Following 5‐fluorouracil (5‐FU), EGF accelerated hematopoietic stem cell regeneration and prolonged survival compared with saline‐treated mice. To mitigate chemotherapy‐induced injury to endothelial cells in vivo, we deleted Baxin VEcadherin+cells (VEcadherinCre;BaxFL/FLmice). Following 5‐FU, VEcadherinCre;BaxFL/FLmice displayed preserved hematopoietic stem/progenitor content compared with littermate controls. 5‐FU and EGF treatment resulted in increased cellular proliferation, decreased apoptosis, and increased DNA double‐strand break repair by non‐homologous end‐joining recombination compared with saline‐treated control mice. When granulocyte colony stimulating factor (G‐CSF) is given with EGF, this combination was synergistic for regeneration compared with either G‐CSF or EGF alone. EGF increased G‐CSF receptor (G‐CSFR) expression following 5‐FU. Conversely, G‐CSF treatment increased both EGF receptor (EGFR) and phosphorylation of EGFR in hematopoietic stem/progenitor cells. In humans, the expression of EGFR is increased in patients with colorectal cancer treated with 5‐FU compared with cancer patients not on 5‐FU. Similarly, EGFR signaling is responsive to G‐CSF in humans in vivo with both increased EGFR and phospho‐EGFR in healthy human donors following G‐CSF treatment compared with donors who did not receive G‐CSF. These data identify EGF as a hematopoietic growth factor following myelosuppressive chemotherapy and that dual therapy with EGF and G‐CSF may be an effective method to accelerate hematopoietic regeneration. StemCells2018;36:252–264 Epidermal growth factor (EGF) is a novel endothelial cell‐derived growth factor that accelerates hematopoietic regeneration following myelosuppressive chemotherapy. Chemotherapy upregulates expression of receptors for both EGF (EGFR) and granulocyte colony stimulating factor (G‐CSFR) on hematopoietic stem and progenitor cells. Treatment with EGF and G‐CSF is synergistic for hematopoietic regeneration compared with either growth factors alone. Dual therapy with EGF and G‐CSF could promote hematopoietic regeneration and decrease cellular apoptosis in select cancer patients to reduce chemotherapy‐induced myelosuppression.