The emergency department (ED) serves as the first point of hospital contact for many septic patients, where risk-stratification would be invaluable. We devised a combination model incorporating demographic, clinical, and heart rate variability (HRV) parameters, alongside individual variables of the Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation II (APACHE II), and Mortality in Emergency Department Sepsis (MEDS) scores for mortality risk-stratification. ED patients fulfilling systemic inflammatory response syndrome criteria were recruited. National Early Warning Score (NEWS), Modified Early Warning Score (MEWS), quick SOFA (qSOFA), SOFA, APACHE II, and MEDS scores were calculated. For the prediction of 30-day in-hospital mortality, combination model performed with an area under the receiver operating characteristic curve of 0.91 (95% confidence interval (CI): 0.88–0.95), outperforming NEWS (0.70, 95% CI: 0.63–0.77), MEWS (0.61, 95% CI 0.53–0.69), qSOFA (0.70, 95% CI 0.63–0.77), SOFA (0.74, 95% CI: 0.67–0.80), APACHE II (0.76, 95% CI: 0.69–0.82), and MEDS scores (0.86, 95% CI: 0.81–0.90). The combination model had an optimal sensitivity and specificity of 91.4% (95% CI: 81.6–96.5%) and 77.9% (95% CI: 72.6–82.4%), respectively. A combination model incorporating clinical, HRV, and disease severity score variables showed superior predictive ability for the mortality risk-stratification of septic patients presenting at the ED.