Acute exposure to systemic poisons represents an important challenge in clinical toxicology. We aimed to analyze the potential role of cardiac biomarkers, routine laboratory tests, and clinical scores as morbidity and in-hospital mortality predictors in patients intoxicated with various systemic poisons. We conducted a prospective study on adults acutely exposed to systemic poisons. We determined the PSS, Glasgow Coma Scale (GCS), and we performed electrocardiogram, laboratory tests, lactate and cardiac biomarkers (which were reassessed 4 h, respectively 6 h later). Of 120 patients included, 45% developed complications, 19.2% had a poor outcome, and 5% died. Multivariate logistic regression sustained lactate (odds ratio (OR) 1.58; confidence interval (CI) 95%: 0.97–2.59; p 0.066), MB isoenzyme of creatine kinase (6h-CKMB; OR 1.08; CI 95%: 1.02–1.16; p 0.018) as predictors for a poor outcome. A GCS < 10 (OR 0.113; CI 95%: 0.019–0.658; p 0.015) and 4h-lactate (OR 4.87; CI 95%: 0.79–29.82; p 0.087) predicted mortality after systemic poisons exposure. Receiver operating characteristic analysis showed that brain natriuretic peptide (area under the curve (AUC), 0.96; CI 95%: 0.92–0.99; p < 0.001), lactate (AUC, 0.91; CI 95%: 0.85–0.97; p < 0.001), and 6h-CKMB have good discriminatory capacity for predicting a poor outcome. In conclusion, these biomarkers, lactate, and GCS can be used to predict morbidity and mortality after systemic poisons exposure.