(1) Introduction: The neutrophil-to lymphocyte ratio is valued as a predictive marker in several inflammatory diseases. For example, an increasing NLR is a risk factor of mortality in sepsis. It also appears to be helpful in other settings such as cancer. The aim of our work was to study the prognostic value of NLR for disease severity and mortality in patients infected with SARS-CoV-2 upon their admission to the Emergency Department (ED) and its early variation (DeltaNLR) in the first 24 h of management (H-24). (2) Methods: Between 1 March and 30 April 2020, we conducted a multicenter and retrospective cohort study of patients with moderate or severe coronavirus disease 19 (COVID-19), who were all hospitalized after presenting to the ED. (3) Results: A total of 1035 patients were included in our study. Factors associated with infection severity were C-reactive protein level (OR: 1.007, CI 95%: [1.005-1.010], p < 0.001), NLR at H-24 (OR: 1.117, CI 95%: [1.060-1.176], p < 0.001), and DeltaNLR (OR: 1.877, CI 95%: [1.160-3.036], p: 0.01). The best threshold of DeltaNLR to predict the severity of infection was 0.222 (sensitivity 56.1%, specificity 68.3%). In multivariate analysis, the only biochemical factor significantly associated with mortality was again DeltaNLR (OR: 2.142, CI 95%: ([1.132-4.056], p: 0.019). The best threshold of DeltaNLR to predict mortality was 0.411 (sensitivity 53.3%; specificity 67.3%). (4) Conclusion: The NLR and its early variation (DeltaNLR) could help physicians predict both severity and mortality associated with SARS-CoV-2 infection, hence contributing to optimized patient management (accurate triage and treatment).