Myeloid-derived suppressor cells (MDSCs) are heterogeneous cell populations that promote tumor development by inhibiting innate and adaptive immunity. Under physiological conditions, neutrophils have a short survival time in vivo. However, G-MDSCs accumulate abnormally in most tumor hosts, and the mechanisms underlying G-MDSC persistence remain to be clarified. This study utilized flow cytometric analysis and in vivo assays to elucidate these mechanisms. It was observed that the apoptosis of G-MDSCs in the peripheral blood of mice was reduced under tumor conditions, whereas an increase in granulocyte colony-stimulating factor (G-CSF) promoted the survival of G-MDSCs. Furthermore, G-CSF reduced the apoptosis of G-MDSCs by activating the Erk/CREB pathway. Thus, inhibition of G-CSF/Erk/CREB signaling may promote the apoptosis of G-MDSCs and shorten their persistence under tumor conditions, as well as attenuate tumor progression.