Vascular adventitial remodeling is an important pathologic process in multiple vascular diseases. Reactive oxygen species (ROS) are an important triggering factor involved in this process. Herein, we investigated whether EETs could prevent the adventitial remodeling via reducing oxidative stress induced by angiotensin II (Ang II). C57BL/6J mice were treated with Ang II by mini-pump to induce vascular remodeling after recombinant adeno-associated virus (rAAV)-mediated CYP2J2 overexpression. Results showed that Ang II treatment significantly induced vascular adventitial remodeling, while CYP2J2 overexpression markedly reduced adventitial hyperplasia, collagen accumulation, phenotype transformation and inward migration of AFs. The similar protective effects of soluble epoxide hydrolase inhibitors (sEHIs), TUPS, on aortic adventitial remodeling were observed as well. In vitro, CYP2J2, TUPS and 11,12-EET significantly prevented primary aortic adventitial fibroblasts (AoAFs) remodeling and oxidative stress induced by Ang II (100nmol/L) via regulating gp91phox, Cu/Zn-SOD and phosphorylation of p38MAPK and JNK. These results suggest that CYP2J2, TUPS and 11,12-EET attenuate vascular adventitial remodeling via direct effects on AoAFs, and the regulation of ROS level was involved in these favorable profiles. Exploitation of this beneficial activity may shed light on designing novel therapeutic approaches for remodeling in multiple kinds of vascular diseases.