Chemokines and chemokine receptors are key mediators of inflammation and important regulators of leukocyte migration in homeostatic conditions as well as during infection and cancer. The atypical receptor ACKR2 is a scavenger receptor for many inflammatory CC chemokines, it is expressed either by non-hematopoietic cells or by hematopoietic cells, and it has been shown to prevent the development of exacerbated inflammatory reactions. In an effort to understand the contribution of this receptor in the regulation of myeloid cell mobilization and myeloid cell effector functions, we investigated the role of ACKR2 in a murine model of myeloid cell mobilization, and in a model of experimental metastasis. The deficiency of ACKR2 was associated with increased mobilization of monocytes and neutrophils from the bone marrow (BM) and with increased number of monocytes confined to BM sinusoids compared to Wild-type (WT) mice. BM chimera experiments showed that the increased mobilization was due to the absence of ACKR2 in the hematopoietic compartment. The analysis of hematopoietic progenitor cells (HPCs) revealed that ACKR2 is expressed by Lin−Sca-1+c-Kit+ cells (LSK) to faint thereafter in more mature myeloid progenitor cells (MPCs) in contrast with the canonical chemokine receptor CCR2. Moreover, HPCs from Ackr2-/- mice expressed higher levels of CCR1, CCR2 and CCR5, but not of CXCR4 and they had higher differentiation rate compared to ACKR2 sufficient LSK. Although neutrophils express low levels of ACKR2 compared to LSK, we found that neutrophils from Ackr2 deficient mice, as well as their HPCs, expressed higher level of CC chemokine receptors and exhibited a more activated phenotype compared to WT. Furthermore, neutrophil depletion and neutrophil adoptive transfer experiments demonstrated that only Ackr2 deficient neutrophils were sufficient to control the metastatic seeding of B16 melanoma cells into the lung. To enhance the metastatic protection observed in Ackr2-/- mice, we treated WT and Ackr2-/- tumor bearing mice with AMD3100, the competitive inhibitor of CXCR4, which is known to induce a rapid neutrophil mobilization from the BM. However, AMD3100 treatment did not further improve the metastatic protection in Ackr2-/- mice, whereas decreased the number of metastases in WT mice. Finally, by using the human promyelocytic cell line HL-60, we demonstrated that ACKR2 directly exerted a negative regulation of CC chemokine receptor expression and cell differentiation. Indeed, HL-60, when transfected with a vector overexpressing ACKR2, had decreased transcript levels of CCR2 and CD11b. These data suggest the ACKR2 is involved in the regulation of chemokine availability and leukocyte recruitment. Moreover, ACKR2 directly controls HPC differentiation, myeloid cell mobilization and their effector function through the inhibition of CC chemokine receptor expression.