Sepsis is a complicated pathological condition in response to severe infections. It is characterized by a strong systemic inflammatory response and multiple components of the immune system are involved. Currently, there is no treatment for sepsis. Platelets are known for their role in hemostasis but they participate in inflammation through cell‐cell interaction and the secretion of inflammatory mediators. Interestingly, an increase in platelet activation, secretion, and aggregation with other immune cells such as monocytes, T lymphocytes, and neutrophils, has been detected in septic patients. Therefore, antiplatelet therapy in terms of P2Y12 antagonists has been evaluated as a possible treatment for sepsis. Overall, blocking P2Y12 decreased platelet marker expression limiting attachment to immune cells in certain studies, but not others. This review underlines the role of platelets during sepsis and whether antagonizing the P2Y12 signaling pathways can alter the outcome. Challenges in studying P2Y12 antagonists in sepsis will also be discussed.