Extensive protein synthesis is required during osteoclast differentiation. Since these nascent proteins are synthesized and folded in the endoplasmic reticulum (ER), ER proteostasis plays a crucial role in this process. ER stress is induced by the accumulation of unfolded or misfolded proteins in the ER lumen. In response, the unfolded protein response (UPR) is activated to reduce this burden, thereby alleviating ER stress. FK506-binding protein (FKBP) 11 is a peptidyl-prolyl isomerase linked to the UPR, but its role in osteoclast differentiation remains unclear. In this study, we found that siRNA-mediated Fkbp11 knockdown reduced osteoclast numbers and osteoclast marker gene expression in RAW264.7 cells. Nfatc1 protein levels were decreased as early as one day after RANKL treatment. Mechanistically, phosphorylated eIF2α, an effector of PERK signaling, was elevated upon Fkbp11 knockdown. Additionally, based on homologous mutations in FKBP10 that cause osteogenesis imperfecta, we constructed FLAG-tagged Fkbp11 mutants (E107K, R109Q, and P129L). In HEK293T cells, E107K and R109Q showed reduced protein levels despite no significant difference in their mRNA expression compared to wild-type Fkbp11. Molecular dynamics simulations suggested no major structural changes in Fkbp11 mutants. These results suggest that Fkbp11 promotes osteoclast differentiation via the regulation of UPR signaling from an early stage, and that the reduced E107K/R109Q protein levels are not primarily explained by reduced mRNA expression or major alterations in overall protein structure. Collectively, these findings provide new insights into the mechanism of osteoclast differentiation and shed light on the relationship between function and mutation within FKBP family proteins.