A key event required for effective resolution of inflammation is efferocytosis, which is defined as phagocytic removal of apoptotic cells mostly by macrophages acquiring an alternatively activated phenotype (M2). c‐Myc has been reported to play a role in alternative activation of human macrophages and is proposed as one of the M2 macrophage markers. We found that M2‐like peritoneal macrophages from zymosan A‐treated mice exhibited a marked accumulation of Myc‐nick, a truncated protein generated by a Calpain‐mediated proteolytic cleavage of full‐ length c‐Myc. Further, ectopic expression of Myc‐nick in murine bone marrow‐derived macrophages promoted the M2 polarization and, consequently, enhanced their efferocytic capability. Notably, Myc‐nick‐induced efferocytosis was found to be tightly associated with α‐tubulin acetylation by K acetyltransferase 2a (Kat2a/Gcn5) activity. These findings suggest Myc‐nick as a novel proresolving mediator that has a fundamental function in maintaining homeostasis under inflammatory conditions.—Zhong, X., Lee, H.‐N., Kim, S. H., Park, S.‐A., Kim, W., Cha, Y.‐N., Surh, Y.‐J. Myc‐nick promotes efferocytosis through M2 macrophage polarization during resolution of inflammation. FASEB J. 32, 5312–5325 (2018). www.fasebj.org