Osteoporosis is the most common and complex skeletal disorder worldwide. Exosomes secreted by bone marrow-derived mesenchymal stromal cells (BMSCs) are considered as an ideal seed source for bone tissue regeneration. However, the role of exosomes secreted by BMSCs (BMSCs-Exos) in osteoporosis and its underlying mechanisms remain unclear. In the present study, the expression of microRNA (miRNA)-146a and circular RNA (circRNA) Rtn4 (circ-Rtn4) was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR), and their protein expression was determined by Western blotting. Enzyme-linked immunosorbent assay was performed to detect caspase-3 activity. Cell viability and apoptosis were assessed using 3-(4,5-Dimethylthiazol-2yl-)-2,5-diphenyl tetrazolium bromide (MTT) assay and flow cytometry analysis, respectively. Luciferase reporter assay was exploited for target validation. Results showed that tumor necrosis factor-α (TNF-α) dose-dependently increased miR-146a expression, inhibited cell viability, and promoted cell apoptosis, as indicated by increased caspase-3, cleaved caspase-3, and Bcl-2-associated X protein (Bax) expression as well as caspase-3 activity. However, miR-146a silencing or co-culture with BMSCs-Exos blocked these effects. Moreover, co-culture with exosomes-derived from circ-Rtn4-modified BMSCs (Rtn4-Exos) attenuated TNF-α-induced cytotoxicity and apoptosis in MC3T3-E1 cells, as evidenced by the decrease in caspase-3, cleaved caspase-3, and Bax protein expression and caspase-3 activity. In addition, miR-146a was identified as a target of circ-Rtn4, and Rtn4-Exos exerted their function in TNF-α-treated MC3T3-E1 cells by sponging miR-146a. Hence, our findings suggested that Rtn4-Exos attenuated TNF-α-induced cytotoxicity and apoptosis in murine MC3T3-E1 cells by sponging miR-146a, suggesting that Rtn4-Exos may serve as novel candidates for treating osteoporosis.