Objective: To investigate the effect of targeted temperature management (TTM) on pyroptosis in patients who achieved return of spontaneous circulation (ROSC) following cardiopulmonary resuscitation (CPR) after cardiac arrest (CA). Methods: This study included 30 patients with CA in whom CPR was initiated within the first 15 minutes after arrest and lasted no longer than 60 minutes, as well as 30 age- and sex-matched healthy volunteers. The study was conducted at Harran University Medical Faculty Hospital between 2021 and 2022. The patient group received TTM therapy for 48 hours. Exclusion criteria were age <18 years, pregnancy, coagulopathy, thrombocytopenia, uncontrolled arrhythmia, end-stage disease, pre-existing neurological disease with cognitive impairment, persistent cardiogenic shock, suspected or confirmed acute intracerebral hemorrhage/acute stroke, and malignancy. Blood samples were collected from patients at three time points: at initiation of TTM (baseline), at 24 hours, and at 48 hours. Serum levels of NLRP3, caspase-1, gasdermin-D, and IL-1β were measured. Results: Serum NLRP3, caspase-1, gasdermin-D, and IL-1β levels were significantly higher in the patient group compared with the control group at all time points. Although not reaching statistical significance, NLRP3, caspase-1, and gasdermin-D levels showed a decreasing trend during the 48-hour follow-up after TTM compared with baseline values. Conclusion: Pyroptosis markers were significantly elevated following cardiac arrest compared with healthy controls. Although the reductions observed after TTM did not reach statistical significance, a downward trend in pyroptosis markers was noted during treatment.