Hepatic ischemia reperfusion (IR) injury causes acute kidney injury (AKI). However, the contribution of AKI to the pathogenesis of liver IR injury is unclear. Furthermore, controversy still exists regarding the role of A(1) adenosine receptors (A(1)ARs) in AKI. In this study, we determined whether exogenous and endogenous A(1)AR activation protects against AKI with subsequent liver protection after hepatic IR in mice. We found that after hepatic IR A(1) knockout (KO) mice and A(1)AR antagonist-treated A(1) wild-type (WT) mice developed worse AKI and liver injury compared with vehicle-treated A(1)WT mice. Moreover, a selective A(1)AR agonist protected against hepatic IR-induced AKI and liver injury in A(1)WT mice. Renal A(1)AR-mediated kidney protection plays a crucial role in protecting the liver after IR because: 1) selective unilateral renal lentiviral overexpression of human A(1)ARs [enhanced green fluorescent protein (EGFP)-huA(1)AR] in A(1)KO mice protected against both kidney and liver injury sustained after liver IR, 2) removal of the EGFP-huA(1)AR lentivirus-injected kidney from A(1)KO mice abolished both renal and hepatic protection after liver IR, and 3) bilateral nephrectomy before hepatic ischemia abolished the protective effects of A(1)AR activation in A(1)WT mice. Finally, inhibition of Akt, but not extracellular signal-regulated kinase mitogen-activated protein kinase, prevented the kidney and liver protection afforded by A(1)AR agonist treatment. Taken together, we show that endogenous and exogenous activation of renal A(1)ARs protect against liver and kidney injury after liver IR in vivo via pathways involving Akt activation.