This study aims to investigate the signaling mechanism involved in high salt (HS)‐induced altered vascular response to adenosine in the presence or absence of adenosine A2A receptor (A2AAR). We hypothesized that HS‐induced enhanced vascular relaxation through A2AAR and epoxy‐eicosatrienoic acid (EETs) is dependent on peroxisome‐proliferator activated receptor‐gamma (PPARγ) and ATP‐sensitive potassium channels (KATP channels) in A2AAR+/+, while, HS‐induced contraction to adenosine is dependent on soluble epoxide hydrolase (sEH) EETs in A2AAR‐/‐ mice. Organ‐bath and Western‐blot experiments were conducted in HS (4% NaCl) and normal salt (NS, 0.18% NaCl)‐fed A2AAR+/+ and A2AAR‐/‐ mice aortae. Enhanced vasodilation to A2AAR agonist, CGS 21680, in HS‐fed A2AAR+/+ mice (+27.6 ± 4.7) was blocked by PPARγ antagonist (0.1 µM T0070907) and KATP channel blocker (10 µM Glibenclamide) to (10.6 ± 1.8% and +4.5 ± 4.9%; p<0.05). sEH inhibitor (AUDA)‐dependent vascular relaxation was mitigated by T0070907 (from +4.1 ± 2.3% to ‐7.1± 3.0 % at 10‐6 M; p<0.05). PPARγ agonist (Rosiglitazone)‐induced relaxation in HS‐A2AAR+/+ mice (+3.5 ± 2.9%) was attenuated by Glibenclamide (‐8.1 ± 1.8% at 10‐6 M; p<0.05). Conversely, HS‐induced contraction to NECA in A2AAR‐/‐ mice (‐57.29 ± 2.84%) was attenuated by AUDA (‐6.62 ± 1.24%, p<0.05). These data implicate the contribution of PPARγ and KATP channels downstream of A2AAR in vascular relaxation in HS‐fed mice while, role of sEH in vascular contraction in HS‐fed A2AAR‐/‐ mice