The complement pathway is an important part of the immune system, and uncontrolled activation is implicated in many diseases. The human complement component 5 protein (C5) is a validated drug target within the complement pathway, as an anti-C5 antibody (Soliris) is an approved therapy for paroxysmal nocturnal hemoglobinuria. Here, we report the identification, optimization and mechanism of action for the first small-molecule inhibitor of C5 complement protein. An inhibitor of the complement pathway of the innate immune system targets the human complement component 5 protein (C5) by binding to an interfacial pocket to prevent its proteolytic cleavage by the last enzyme of the complement pathway, C5 convertase.