Atherosclerosis (AS) progression is closely linked to oxidized low-density lipoprotein (Ox-LDL)-induced endothelial cell injury. This study investigates the molecular mechanism by which the PCSK9 inhibitor Evolocumab (EVC) alleviates AS. We used Ox-LDL-induced HUVECs and high-fat diet (HFD)-fed ApoE-/- mice as in vitro and in vivo AS models. AS plaque formation was detected by HE and Oil Red O staining. The levels of lipid indicators and oxidative stress-related factors were measured via ELISA. The expression levels of PCSK9, apoptosis-related proteins, and signaling pathway-related proteins were determined via Western blotting. The result shows that EVC improved blood lipids and alleviated aortic injury in atherosclerotic mice, and concomitantly suppressed Ox-LDL-induced apoptosis and oxidative stress in HUVECs. In terms of the molecular mechanism, EVC attenuated the Ox-LDL-induced phosphorylation of ERK1/2, JNK and p38. Both the ROS inhibitor N-acetylcysteine and the p38 MAPK signaling pathway inhibitor SB203580 can enhance the suppressive effect of the PCSK9 inhibitor EVC on Ox-LDL induced apoptosis and oxidative stress in HUVECs, while the p38 MAPK signaling pathway activator C16-PAF shows the opposite results. In conclusion, the PCSK9 inhibitor EVC inhibits Ox-LDL-induced HUVECs apoptosis and oxidative stress by inhibiting the ROS/MAPK signaling pathway, thereby alleviating the progression of AS.