Coronary reactive hyperemia (CRH) protects the heart against ischemia. Adenosine A_2AAR-deficient (A_2AAR^-/-) mice have increased expression of soluble epoxide hydrolase (sEH); the enzyme responsible for breaking down the cardioprotective epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs). sEH-inhibition enhances CRH, increases EETs, and modulates oxylipin profiles. We investigated the changes of oxylipins and their impact on CRH in A_2AAR^-/- and wild type (WT) mice. We hypothesized that the attenuated CRH in A_2AAR^-/- mice is mediated by changes in oxylipin profiles, and that it can be reversed by either sEH- or ω-hydroxylases-inhibition. Compared to WT mice, A_2AAR^-/- mice had attenuated CRH and changed oxylipin profiles, which were consistent between plasma and heart perfusate samples, including decreased EET/DHET ratios, and increased hydroxyeicosatetraenoic acids (HETEs). Plasma oxylipns in A_2AAR^-/- mice indicated an increased proinflammatory state including increased ω-terminal HETEs, decreased epoxyoctadecaenoic/dihydroxyoctadecaenoic acids (EpOMEs/DiHOMEs) ratios, increased 9-hydroxyoctadecadienoic acid, and increased prostanoids. Inhibition of either sEH or ω-hydroxylases reversed the reduced CRH in A_2AAR^-/- mice. In WT and sEH^-/- mice, blocking A_2AAR decreased CRH. These data demonstrate that A_2AAR-deletion was associated with changes in oxylipin profiles, which may contribute to the attenuated CRH. Also, inhibition of sEH and ω-hydroxylases reversed the reduction in CRH.