The aim of the present study is to investigate the effect and the underlying mechanism of recombinant human fibroblast growth factor 18 (rhFGF18) on postmenopausal osteoporosis. The effect of rhFGF18 on the proliferation of osteoblastic cell line MC3T3-E1 and its related mechanism were examined. The oxidative stress model of MC3T3-E1 was established using hydrogen peroxide to evaluate the protective effect of rhFGF18. Flow cytometry was employed to detect cell apoptosis, while the protein expressions of Bcl-2, Bax and caspase-3 were detected by Western blotting. Furthermore, we performed ovariectomy (OVX) on ICR mice to imitate estrogen-deficiency postmenopausal osteoporosis. Bone metabolism and bone morphological parameters in OVX mice were evaluated. Our in vitro study showed that rhFGF18 promoted MC3T3-E1 cells proliferation by activating extracellular signal-regulated kinase (ERK) and p38 instead of c-Jun N-terminal kinase (JNKs). rhFGF18 prevented cell damage from oxidative stress via the inhibition of apoptosis. After rhFGF18 administration, the expression level of anti-apoptotic protein Bcl-2 was upregulated, whereas pro-apoptotic proteins Bax and caspase-3 were all downregulated. Administrating rhFGF18 also improved bone metabolism and bone morphological parameters in OVX mice. Thus, rhFGF18 can effectively prevent bone loss in OVX mice by enhancing osteoblastogenesis and protects osteoblasts from oxidative-stress-induced apoptosis.