Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor with an important role in lipid metabolism, inflammation and cardiovascular diseases. PPARγ ligands have inhibitory effects on platelet aggregation via the cAMP pathway, which may confer them a protective cardioprotective role. Edaglitazone and Ciglitazone are two chemically-similar thiazolidinedione (TZD) drugs that have been described as potent PPARγ agonists; however, Edaglitazone is over 100 times more potent than Ciglitazone. Here, we report a computational study to describe the ligand binding and the experimental antiplatelet profiles of Edaglitazone and Ciglitazone. Both ligands presented similar orientations within the PPARγ binding site. Their polar heads exhibit complex hydrogen bond networks with the residues at arm I pocket, while their hydrophobic tails are oriented inside arm II or the entrance pocket. The bulkier and longer tail of Edaglitazone exhibited additional hydrophobic interactions, explaining its stronger binding to PPARγ supported by binding affinity calculations. On the other hand, both Edaglitazone and Ciglitazone displayed an antiplatelet activity, but only Edaglitazone retained such effect at low concentrations. Furthermore, we evidenced that Edaglitazone increases intraplatelet cAMP levels and prevents PPARγ secretion, explaining its greater antiplatelet activity. Altogether, the more potent PPARγ agonist Edaglitazone seems to be a potent antiplatelet agent.