Cardiopulmonary resuscitation (CPR) involves a series of urgent life‑saving actions performed to manually revive a person in cardiac arrest. In >70% of CPR cases, the primary health deterioration is due to acute myocardial infarction or a significant pulmonary embolism. Fibrinolytic therapy, also known as thrombolytic treatment, functions by dissolving dangerous intravascular clots to mitigate ischemic damage through improved blood circulation. Thrombolytic therapy has emerged as a promising intervention within the context of CPR for patients experiencing cardiac arrest. Recombinant tissue plasminogen activator (rtPA) is a bioengineered version of a natural enzyme that converts plasminogen into plasmin, an enzyme essential for clot dissolution. The efficacy of rtPA in thrombolytic therapy for CPR suggests its potential as a valuable clinical tool. The present comprehensive review assessed the efficacy and safety of rtPA administration during CPR, focusing on outcomes such as survival rates, neurological function and potential complications. It also explored the underlying mechanisms by which rtPA may enhance reperfusion and improve patient outcomes, including clot dissolution, myocardial salvage and microcirculatory improvements. Additionally, it examined the optimal timing and dosing strategies for rtPA administration and its integration with standard CPR protocols and other supportive therapies.