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We report that acetyl‐n‐Ser‐Asp‐Lys‐Pro (AcSDKP), which removes progenitor cells from cell cycle, in combination with granulocyte‐colony stimulating factor (G‐CSF) can significantly improve myelorestoration following irradiation (7 Gy). Peripheral blood, spleen and bone marrow (BM) cell recovery and progenitor cell reconstitution [IL‐3‐responsive colony‐forming cells (CFC) and high proliferative potential colony‐forming cells (HPP‐CFC)] were studied. Studies on the optimal schedule of AcSDKP administration revealed maximal effects on progenitor cells when AcSDKP was administered as a continuous infusion for 3 d starting 24 h prior to irradiation and used in combination with G‐CSF. The numbers of CFC and HPP‐CFC in the BM were significantly increased following irradiation in mice receiving AcSDKP and G‐CSF as compared to either drug alone. The numbers of CFC in the spleen were significantly increased in mice receiving AcSDKP and G‐CSF on days 10 and 14 as compared to AcSDKP alone, but not G‐CSF. Similarly, CFC and HPP‐CFC in the spleen were significantly increased in mice receiving AcSDKP and G‐CSF on day 18 as compared to mice receiving PBS and G‐CSF. These studies suggest that AcSDKP in combination with G‐CSF may have potential for the protection of progenitor cells in patients undergoing intensive chemo‐ and/or radiotherapy.