Atherosclerosis is an important pathological condition which is accompanied by a vascular smooth muscle cell (VSMC) phenotype switch toward a synthetic phenotype. As an acute-phase protein, Serum Amyloid A (SAA) is thought to have a close relationship to atherosclerosis development. However, no study has investigated the direct effect of SAA on the VSMC phenotype switch, as well as the underlying mechanisms. The purpose of our study was to explore the effect of SAA on the VSMC phenotype switch and the potential mechanisms involved. In our study, we found that SAA induced the VSMC phenotype switch which reduced expression of the smooth muscle cell (SMC) marker and enhanced expression of the matrix synthesis related marker. The proliferative ability of VSMCs was also increased by SAA treatment. Furthermore, our research found that SAA activated the ERK1/2 and p38 MAPK signaling pathways. Finally, by applying the ERK1/2 and p38 inhibitors, U0126 and SB203580, we demonstrated that the SAA-induced VSMC phenotype switch was p38-dependent. Taken together, these results indicated that SAA may play an important role in promoting the VSMC phenotype switch through the p38 MAPK signaling pathway.