AbstractTristetraprolin (TTP; also known as NUP475, GOS24, or TIS11), encoded by Zfp36, is an RNA‐binding protein that regulates target gene expression by promoting mRNA decay and preventing translation. Although previous studies have indicated that TTP deficiency is associated with systemic inflammation and a catabolic‐like skeletal phenotype, the mechanistic underpinnings remain unclear. Here, using both TTP‐deficient (TTPKO) and myeloid‐specific TTPKO (cTTPKO) mice, we reveal that global absence or loss of TTP in the myeloid compartment results in a reduced bone microarchitecture, whereas gain‐of‐function TTP knock‐in (TTPKI) mice exhibit no significant loss of bone microarchitecture. Flow cytometry analysis revealed a significant immunosuppressive immune cell phenotype with increased monocytic myeloid‐derived suppressor cells (M‐MDSCs) in TTPKO and cTTPKO mice, whereas no significant changes were observed in TTPKI mice. Single‐cell transcriptomic analyses of bone marrow myeloid progenitor cell populations indicated a dramatic increase in early MDSC marker genes for both cTTPKO and TTPKO bone marrow populations. Consistent with these phenotypic and transcriptomic data, in vitro osteoclastogenesis analysis of bone marrow M‐MDSCs from cTTPKO and TTPKO displayed enhanced osteoclast differentiation and functional capacity. Focused transcriptomic analyses of differentiated M‐MDSCs showed increased osteoclast‐specific transcription factors and cell fusion gene expression. Finally, functional data showed that M‐MDSCs from TTP loss‐of‐function mice were capable of osteoclastogenesis and bone resorption in a context‐dependent manner. Collectively, these findings indicate that TTP plays a central role in regulating osteoclastogenesis through multiple mechanisms, including induction of M‐MDSCs that appear to regulate skeletal phenotype.