The secreted frizzled‑related protein 2 (SFRP2) has been reported to inhibit non‑small cell lung cancer (NSCLC) cell survival and metastasis; however, the underlying mechanisms are yet to be fully determined. The present study focused on mitochondrial fission and the Wnt signaling pathway. The results demonstrated that SFRP2 was downregulated in the NSCLC cell line A549 compared with in a normal pulmonary epithelial cell line using western blotting, reverse transcription‑quantitative PCR and immunofluorescence. Subsequently, it was demonstrated that SFRP2 overexpression promoted the apoptosis, and inhibited the proliferation and metastasis of A549 cells using MTT assays, TUNEL staining and 5‑ethynyl‑2'‑deoxyuridine labeling. At the molecular level, the overexpression of SFRP2 in A549 cells led to the activation of mitochondrial fission by inhibiting the Wnt signal pathway. Excessive mitochondrial fission induced low ATP generation, impaired mitochondrial respiratory function, induced mitochondrial potential depolarization, and increased mitochondrial permeability transition pore opening, and imbalances in pro‑ and antiapoptotic protein expression. Furthermore, mitochondrial fission was involved in the inhibition of A549 cell proliferation and metastasis. Thus, SFRP2 may inhibit the survival and metastasis of NSCLC cells via the Wnt/mitochondrial fission pathway.