Adenosine receptors (ARs) are integral components of various physiological processes and are thus clinical targets for the treatment of tumours and inflammatory-related disorders. Despite the progress achieved in therapeutic development against this diverse receptor family, the development of drugs targeting ARs has encountered challenges, including limited efficacy, preferential binding affinities, and notable side effects. In this study, we present three cryo-electron microscopy (cryo-EM) structures of the A3 adenosine receptor (A3AR) in distinct states, including two A3AR structures complexed with its endogenous ligand, adenosine, and a selective agonist, PICLIDENOSON, along with a cryo-EM structure of A3AR bound to the covalent antagonist LUF7602. By comparing A3AR structures in different states, molecular mechanisms of agonism and antagonism were revealed. Together with other solved AR structures and binding analyses, we provide a comprehensive understanding of how ligands interact with A3AR in various states, ultimately revealing the key determinants responsible for ligand recognition and selectivity among different AR subtypes.