Cardiac fibrosis is a significant global health problem that occurs after pathological stimuli to the cardiovascular system. Previous researchers have shown the protective role of Salvia miltiorrhiza Bunge (Danshen) as well as its extracted compound Tanshinone IIA (Tan IIA) against cardiac fibrosis. However no previous work has shown the effects of Tanshinone IIA on cardiac cytoskeleton or the possible relations with its role on cardiac fibrosis. The present study confirms that Tan IIA inhibits the pro iferation of mouse cardiac fibroblasts in cultures by MTT assay. It was also observed that Tan IIA decreases β-tubulin expression, especially in the perinuclear area of fibroblasts. Furthermore, we presented by Western blot that TanII A attenuates VEGF expression through HIF-1α and Keap1-Nrf2 pathways, which could be the underlying mechanisms of the Tan IIA's role on cardiac fibrosis. This work demonstrated, for the first time, that the protective role of TanII A against cardiac fibrosis through inhibition of cardiac β-tubulin involves regulation on the antioxidant pathways.