Background: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) has shown constant incidence throughout time, despite advances in endoscopic technology, devices, or personal skills of the operating endoscopists, with prevention and prediction of severity in PEP being constant concerns. Several prospective studies have investigated the role of systemic inflammatory response syndrome (SIRS) criteria or the quick Sequential Organ Failure Assessment (qSOFA) score in the PEP severity assessment. However, there are no clearly defined tools for the prediction of PEP severity. Methods: A total of 403 patients were prospectively monitored 60 days after ERCP for the detection of PEP development. Consequently, we evaluated the lengths of stay, incidence of organic dysfunction, and mortality rates of these patients. The predictive power of the univariate model was evaluated by using the receiver operating characteristic curve and analyzing the area under the curve (AUC). Results: Incidence of PEP was similar to that reported in the majority of trials. The 60-day survival rate of PEP patients reached 82.8%. A qSOFA score ≥ 1 is a very good predictor for organ dysfunction (AUC 0.993, p < 0.0001). SIRS can also be considered a significant predictor for organic dysfunctions in PEP patients (AUC 0.926, p < 0.0001). However, only qSOFA was found to significantly predict mortality in PEP patients (AUC 0.885, p = 0.003), with SIRS criteria showing a much lower predictive power. Neither SIRS nor qSOFA showed any predictive value for the length of stay of PEP patients. Conclusion: Our study offers novel information about severity prediction in PEP patients. Both SIRS criteria and qSOFA showed good predictive value for organic dysfunction, mortality, and hospitalization.