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Background Omega‐3 polyunsaturated fatty acids (ω3 PUFA s) suppress inflammation through activation of free fatty acid receptor 4 ( FFAR 4), but this pathway has not been explored in the context of cardiovascular disease. We aimed to elucidate the involvement of FFAR 4 activation by ω3 PUFA s in the process of vascular inflammation and neointimal hyperplasia in mice. Methods and Results We used mice with disruption of FFAR 4 ( Ffar4 −/− ), along with a strain that synthesizes high levels of ω3 PUFA s ( fat‐1 ) and a group of crossed mice ( Ffar4 −/− / fat‐1 ), to elucidate the role of FFAR 4 in vascular dysfunction using acute and chronic thrombosis/vascular remodeling models. The presence of FFAR 4 in vascular‐associated cells including perivascular adipocytes and macrophages, but not platelets, was demonstrated. ω3 PUFA s endogenously generated in fat‐1 mice (n=9), but not in compound Ffar4 −/− / fat‐1 mice (n=9), attenuated femoral arterial thrombosis induced by FeCl 3 . Neointimal hyperplasia and vascular inflammation in the common carotid artery were significantly curtailed 4 weeks after FeCl 3 injury in fat‐1 mice (n=6). This included greater luminal diameter and enhanced blood flow, reduced intima:media ratio, and diminished macrophage infiltration in the vasculature and perivascular adipose tissue compared with control mice. These effects were attenuated in the Ffar4 −/− / fat‐1 mice. Conclusions These results indicate that ω3 PUFA s mitigate vascular inflammation, arterial thrombus formation, and neointimal hyperplasia by interaction with FFAR 4 in mice. Moreover, the ω3 PUFA – FFAR 4 pathway decreases inflammatory responses with dampened macrophage transmigration and infiltration.