Safflower yellow (SY) has been widely used in Chinese medicine for the treatment of ischemic cardiocerebrovascular disease. Recent studies have indicated that SY has a reverse effect on vascular remodeling (VR). However, its detailed mechanisms require further study to provide more scientific evidence for the clinical treatment of VR. This study aims to investigate the effects of SY on angiotensin II (Ang II)-induced cell proliferation, migration, apoptosis, and extracellular matrix in rat aortic adventitial fibroblasts (AFs). The proliferation and migration rates of AFs treated with Ang II for 24 h were higher than those of untreated AFs; and increases in the expression of p-ERK1/2, AP-1, collagen I, and collagen III were observed. Treatment with SY significantly downregulated cell proliferation, migration, and the expression of p-ERK1/2, AP-1, collagen I, and collagen III. We also found that the cell percentage of apoptosis of AFs treated with Ang II for 24 h was lower than those of untreated AFs. After treatment with SY, the percentage of apoptosis was increased. SY exhibits anti-proliferative, anti-migratory, and pro-apoptotic activities in rat aortic AFs, perhaps through the Ang II/ERK/AP-1 signaling pathway. The present findings may provide new clues regarding the potential function of SY to treat or prevent VR.