Epidemiological studies suggest that the intake of natural/nutrient products is inversely related to cancer risk. While oxidative stress, generating reactive oxygen species, has been linked to cancer initiation and progression, dietary antioxidants have reduced the risk of certain cancers. Experimental studies have demonstrated that antioxidants and phytochemicals could prevent cancer metastasis, and antioxidants were suggested as adjuvants in cancer therapy. Ganoderma lucidum is an Asian medicinal mushroom that has been used for the past two thousand years for the treatment of various diseases, including cancer. G. lucidum is currently popular as a dietary supplement in the form of tea, powder or extract. We have previously demonstrated that G. lucidum suppresses growth, angiogenesis and invasiveness of highly invasive and metastatic breast cancer cells. The present study was undertaken to evaluate the effect of G. lucidum on oxidative stress-induced metastatic behavior of poorly-invasive MCF-7 breast cancer cells. We show that G. lucidum inhibits oxidative stress-induced migration of MCF-7 cells by the down-regulation of MAPK signaling. G. lucidum suppressed oxidative stress stimulated phosphorylation of extracellular signal-regulated protein kinases (Erk1/2), which resulted in the down-regulation of expression of c-fos, and in the inhibition of transcription factors AP-1 and NF-kappaB. The biological effect of G. lucidum on cell migration was mediated by the suppression of secretion of interleukin-8 from MCF-7 cells exposed to oxidative stress. In summary, our results suggest that G. lucidum inhibits the oxidative stress-induced invasive behavior of breast cancer cells by modulating Erk1/2 signaling and can be potentially considered as an antioxidant in adjuvant cancer therapy.