Background: Acute pulmonary embolism (APE) is a condition that can be fatal. The severity of the disease influences therapeutic decisions, and mortality varies significantly depending on the condition’s severity. Identification of patients with a high mortality risk is crucial. Since inflammation, hemostatic, and coagulation abnormalities are linked to APE, serum biomarkers may be helpful for prognostication. Aim: To evaluate the significance of serum biomarkers in APE risk assessment and the suitability of these biomarkers for management and decision-making. Methods: This study involved 60 adult patients with APE who were divided according to risk categorization. It was conducted in Chest, Cardiology and Internal Medicine department, Zagazig University Hospitals from December 2022 to May 2023. Several hematological biomarkers and their significance in APE risk assessment were measured with a comparison with the latest risk stratification methods which include haemodynamic measures and right ventricular (RV) dysfunction echocardiographic markers. Results: Each risk group involved 20 patients (high, intermediate (10 were intermediate-high and 10 were intermediate-low) and low risk group). They were 34 females and 26 males with the mean ± SD of their age was 59.25 ± 13.06 years. Regarding hematological biomarkers, there were statistically significant differences as regards; lymphocytes, platelet to lymphocyte ratio (PLR), albumin, blood urea nitrogen (BUN), C-reactive protein (CRP) and D-dimer with highly statistically significant differences as regards; neutrophil to lymphocyte ratio (NLR), BUN to albumin (B/A) ratio, troponin I (TnI), and brain natriuretic peptide (BNP). TnI had the highest specificity and predictive value positive (PVP) and BNP had the highest sensitivity and predictive value negative (PVN) in predicting high risk groups. The Lymphocyte and NLR showed the lowest sensitivity and the albumin and B/A ratio had the lowest specificity. Regarding transthoracic echocardiography (TEE); there was a statistically significant increase regarding pulmonary artery systolic pressure (PASP) and a highly statistically significant increase regarding the right ventricle/left ventricle (RV/LV) ratio. There were statistically significant decreases regarding tricuspid annular plane systolic excursion (TAPSE) and peak systolic velocity of tricuspid annulus (S′) among risk groups. Conclusion: APE prognosis can be judged accurately by simultaneously measuring a few biomarkers along with haemodynamic variables and echocardiographic parameters of RV dysfunction.