During chronic inflammation, macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) have well established effects on gene networks that stimulate osteoclastogenesis, which is the culprit of several bone diseases. In this study, we investigated the anti-osteoclastogenic effects in vitro of oleuropein (OL) and its peracetylated derivative (Per-OL) by exploring the expression level of key hub genes involved in fate decision and lineage commitment, differentiation, and function of human blood monocyte-derived osteoclasts. Monocytes were purified from peripheral blood mononuclear cells of healthy individuals using commercial antibodies coated with magnetic beads and treated with M-CSF/RANKL in the presence or absence of OL or Per-OL (25 and 50 μM) for 6 days. We demonstrated that OL and especially Per-OL impair transcriptional gene circuits able to support osteoclastogenesis from human blood monocytes. Our results indicate that OL and notably Per-OL are promising candidates to control osteoclastogenesis.