Macrophages are classified mainly into two subtypes, M1 and M2, which exhibit distinct phenotypes, based on their microenvironment. Although recent studies have suggested that G-protein-coupled receptors (GPCRs) are associated with M1/M2 macrophage polarization, available information on GPCR-mediated macrophage polarization is still limited. In the present study, we identified Gpr137b as an orphan GPCR abundantly expressed in RAW264, a mouse macrophage cell line, and illuminated its role in M2 macrophage polarization. We generated Gpr137b-knockout (Gpr137b-KO) clones of RAW264 cells using the CRISPR/Cas9 genome editing system. Two independent Gpr137b-KO clones were isolated, which were demonstrated to have frameshifting 188-nucleotide deletions at a region containing the ATG start codon of Gpr137b. Consistently, qRT-PCR analysis revealed that the deleted region is not transcribed. We then treated the Gpr137b-KO and wildtype RAW264 cells with interleukin-4 (IL-4) to induce M2 macrophage polarization. Microarray analysis revealed that the IL-4-induced gene expression of representative M2 macrophage markers was significantly reduced in the Gpr137b-KO cells, and this was validated by qRT-PCR analysis. By contrast, M1 macrophage marker gene expression induced by lipopolysaccharide was unaffected by Gpr137b-KO. Collectively, the current study shows that Gpr137b is a possible regulator of M2 macrophage polarization.