Background and Purpose: Tau pathology is instrumental in the gradual loss of neuronal functions and cognitive decline in tauopathies, including Alzheimer’s disease (AD). Adenosine homeostasis is essential to brain metabolism and plasticity but the link to Tau remained ill-defined. Herein, we aimed at investigating whether modulating adenosine tone, through pharmacological manipulation of equilibrative nucleoside transporter 1 (ENT1), impacts Tau pathology, associated molecular alterations, and subsequent neurodegeneration. Experimental Approach: Thy-Tau22 and their littermate controls were continuously treated with J4, an ENT1 inhibitor, in drinking water. The animal behavior and electrophysiological recording were employed to evaluate the memory function and synaptic plasticity in the hippocampus. We have then conducted phospho-proteomics, immunohistological investigations, and bulk RNA-seq analysis to evaluate the mode of action of J4. Key Results: We demonstrated that treatment with J4 not only reduced Tau hyperphosphorylation and improved memory deficits and synaptic plasticity but also normalized mitochondrial dysfunction, synaptic loss, and abnormal expression of immune-related gene signatures in the Thy-Tau22 mice. These beneficial effects were particularly ascribed to the ability of J4 to suppress the overactivation of AMPK, suggesting that normalization of energy dysfunction mitigates neuronal dysfunctions in Tauopathy. Mechanisms targeted by J4 such as AMPK overactivation and neurotoxic astrocyte phenotype were found in brains from patients with primary tauopathies and AD. Conclusion and Implications: The present data, therefore, support an instrumental link between energy dysfunction and adenosine homeostasis in tauopathy. Together, our data support that targeting adenosine metabolism is a novel reliable strategy for tauopathies.