The phenolic profiles of extra virgin olive oils (EVOOs) may influence their cardiovascular benefits. In a randomized crossover of acute EVOO intake on platelet function, participants (n = 9) consumed 40 mL of EVOO weekly. EVOOs were matched for total phenolic content and were either tyrosol-poor with 1:2 oleacein/oleocanthal (D2i0.5), or 2:1 oleacein/oleocanthal (D2i2), or predominantly tyrosol (D2i0). Ibuprofen provided a platelet inhibition control. Blood was collected pre- and 2 h post-EVOO intake. D2i0.5 and D2i2 reduced 1 µg/mL collagen-stimulated maximum platelet aggregation (Pmax), with effects best correlated to oleocanthal intake (R = 0.56, P = 0.002). Total phenolic intake was independently correlated to eicosanoid production inhibition, suggesting that cyclooxygenase blockade was not responsible for the Pmax inhibition. Five participants exhibited >25% ΔPmax declines with D2i0.5 and D2i2 intake and plasma metabolomic profiles discriminated subjects by oil responsivity. Platelet responses to acute EVOO intake are associated with oil phenolic composition and may be influenced by diet.