Caffeic Acid Phenethyl Ester (CAPE), an antioxidant flavonoid isolated from hives of honeybee, is reported to exert its anti-osteogenic function by inhibiting the NF-kB activation. It also disrupts the microtubule network created by osteoclasts, which would also aid in the attenuation of bone resorption. However, commercially available parental CAPE molecules are highly insoluble and have low stability. Recent studies have shown that a new fluorinated derivative of CAPE (F-CAPE) exhibited improved NF-kB inhibition and stability. Herein we have investigated the anti-osteoclastogenic activity of F-CAPE using an in vitro osteoclastogenesis model with mouse monocytic cell line (RAW264.7 cells). We observed an increased dose dependent inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL)-induced multinuclear tartarate resistant acid phosphatase (TRAP) positive osteoclast formation by F-CAPE compared to the parental compound. F-CAPE at 150nM concentration has shown more than 2 fold higher anti-osteoclastogenic activity compared to CAPE. Western blot analysis revealed that F-CAPE decreased the expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are the master regulators during osteoclastogenesis. In addition, F-CAPE inhibits the NF-κB signaling pathway, as confirmed by the decreased degradation of IκBα. Our data suggests that F-CAPE is a highly potent anti-osteogenic compound and could be a novel therapeutic molecule to attenuate excessive bone degradation during autoimmune arthritis.