Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease in which blood cells lack anchored proteins that regulate the complement system. The erythrocytes are then destroyed because of uncontrolled complement activity, leading to intravascular hemolysis (IVH) and a high risk of thrombosis outcome. A huge alteration in the treatment of the disease was the development of terminal complement inhibitors, with the achievement of IVH blockade, reduction or abolishment of red blood cell (RBC) transfusions, and thromboembolic events prevention. However, patients treated with these inhibitors can still present extravascular hemolysis (EVH) caused by C3 activation and residual IVH or clinically relevant levels of breakthrough hemolysis (BTH). Proximal complement inhibitors turned out to be the key to the solution of this problem by targeting components of the proximal complement pathway, avoiding intra and extravascular hemolysis. FDA approved eculizumab, ravulizumab (terminal inhibitors), pegcetacoplan, iptacopan, and danicopan (proximal inhibitors) as a treatment for PNH so far. Various clinical trials are underway to find the most effective method to treat patients with PNH. This review aimed to summarize 71 registered clinical trials in the ClinicalTrials.gov database with the various treatment drugs, possible mechanisms, and novel findings related to PNH treatment.