Perfluorocarbon nanodroplets (PFC NDs) are submicrometre particles comprising a liquid perfluorocarbon core stabilised by a phospholipid shell, with emerging potential for therapeutic targeted gas delivery and drug delivery. While related PFC microbubbles have demonstrated promise in drug delivery applications, including bone repair, the biological effects and translational relevance of PFC nanodroplets in skeletal systems remain untested. This study investigated the effects of nanodroplets on bone cell viability in vitro and on osteoclastogenesis under normoxic and hypoxic conditions. Confocal microscopy and flow cytometry were used to assess nanodroplet association with skeletally-relevant MC3T3-E1 and Saos-2 osteoblastic cell lines, human bone-marrow-derived stromal cells, and peripheral blood mononuclear cell-derived osteoclasts. Cellular viability and differentiation were evaluated using Alamar Blue, TRAP, and DAPI staining. Long-term (12-day) nanodroplet exposure significantly reduced osteoclast number in both normoxia and hypoxia, whereas short-term exposure in hypoxia increased osteoclast formation. Importantly, nanodroplets did not adversely affect osteoblastic viability. In summary, these findings indicate that PFC nanodroplets are compatible with key skeletal cell populations and can modulate osteoclastogenesis in a context-dependent manner, supporting their potential as vehicles for bone-targeted gas or drug delivery.