In this study, we sought to characterize tenofovir’s actions in two murine models of fibrosis and report four novel findings: 1) Tenofovir’s impact on fibrosis is independent of its viral suppression capabilities; 2) Tenofovir prevents hepatic fibrosis development in a murine model of hepatotoxin-induced fibrosis; 3) Tenofovir protects against bleomycin-induced dermal fibrosis; 4) Tenofovir blocks Pannexin-1-mediated cellular ATP release leading to diminished adenosine levels in the extracellular space which diminishes A2AR-mediated fibrosis. Here, ADORA2A is linked to Hepatic fibrosis.