Ticagrelor is a potent antagonist of the P2Y12 receptor (P2Y12R) and consequently an inhibitor of platelet activity effective in the treatment of atherothrombosis. Here, we sought to further characterise its molecular mechanism of action. Initial studies showed that ticagrelor promoted a greater inhibition of ADP-induced Ca2+ release in washed platelets versus other P2Y12R antagonists. This additional effect of ticagrelor beyond P2Y12R antagonism was in part as a consequence of ticagrelor inhibiting the equilibrative nucleoside transporter 1 (ENT1) on platelets, leading to accumulation of extracellular adenosine and activation of Gs-coupled adenosine A2A receptors. This contributed to an increase in basal cAMP and VASP phosphorylation. In addition, ticagrelor increased platelet cAMP and VASP phosphorylation in the absence of ADP in an adenosine receptor-independent manner. We hypothesised that this increase originated from a direct effect on basal agonist-independent P2Y12R signalling, and this was validated in 1321N1 cells stably transfected with human P2Y12R. In these cells, ticagrelor blocked the constitutive agonist-independent activity of the P2Y12R, limiting basal Gi-coupled signalling and thereby increasing cAMP levels. These data suggest that ticagrelor has the pharmacological profile of an inverse agonist. Based on our results showing insurmountable inhibition of ADP-induced Ca2+ release and forskolin-induced cAMP, the mode of antagonism of ticagrelor also appears non-competitive, at least functionally. In summary, our studies describe two novel modes of action of ticagrelor, inhibition of platelet ENT1 and inverse agonism at the P2Y12R that contribute to its effective inhibition of platelet activation.