Background: Cardiac and neurological insults induced by carbon monoxide (CO) poisoning are the main reasons for elevated mortality rates and morbidities. Accordingly, identifying high-risk patients is crucial. This work aims to enhance clinical management and predict outcomes in patients with CO poisoning. Subjects and Methods: A prospective cohort study, conducted at Zagazig University Hospital (ZUH) on 36 cases of acute CO poisoning, categorized according to their outcome into two groups: those with complications (7 cases) and those without complications (29 cases). Circulating biomarkers were measured for all participants. Results: The mortality rate was 8.3%. Approximately 80.6% recovered without complications. Carboxyhemoglobin (COHb), lactate, and malondialdehyde levels were significantly correlated with the outcome. Biomarker performance, as evaluated by receiver operating characteristic (ROC) curve analysis, showed that creatine kinase-MB (CK-MB) had an accuracy of 86.11% and an area under the curve (AUC) of 0.79. N terminal pro-brain natriuretic peptide (NT-Pro BNP) demonstrated an accuracy of 77.78% and an AUC of 0.91, while troponin T exhibited an accuracy of 72.22% and an AUC of 0.81. In addition, creatine phosphokinase (CPK) had an accuracy of 97.22% and an AUC of 1, whereas neuron-specific enolase (NSE) showed an accuracy of 83.33% and an AUC of 0.89. The neutrophil lymphocyte ratio (NLR) had 77.78% accuracy, with an AUC of 0.82, similar to the glucose/potassium ratio (G/K ratio). Conclusions: CPK and NT-Pro BNP demonstrated excellent validity in predicting outcomes of CO poisoning. NSE, NLR, G/K ratio, and troponin T exhibited good validity, while CK-MB showed fair validity.