After resuscitation from cardiac arrest, a combination of the complex pathophysiologic process, known as post-cardiac arrest syndrome (PCAS), is attributed to multiple organ damage. Global ischemic cascade occurs in the brain due to generalized ischemia during cardiac arrest and the reperfusion process after the return of spontaneous circulation (ROSC), leading to hypoxic/ ischemic brain injury. Targeted temperature management (TTM) is a well-known neuroprotective therapy for ischemic/hypoxic brain injury. This global brain injury is a significant cause of death in PCAS. The implementation of TTM for PCAS leads to a reduction in mortality and better clinical outcomes among survivors. Prognostication is an essential part of post-resuscitation care. Before the TTM era, physicians relied on the algorithm for prognostication in comatose patients released by the American Academy of Neurology in 2006. However, TTM also announced more significant uncertainty during prognostication. During this TTM era, prognostication should not rely on just a solitary parameter. The trend of prognostication turns into a multimodal strategy integrating physical examination with supplementary methods, consisting of electrophysiology such as somatosensory evoked potential (SSEP) and electroencephalography (EEG), blood biomarkers, particularly serum neuron-specific enolase (NSE), and neuro-radiography including brain imaging with CT/MRI, to enhance prognostic accuracy.