Background/Objectives: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to pose a significant global health challenge due to its high transmissibility and potential for severe clinical outcomes. Early identification of patients at risk of hospitalization is essential for effective triage in emergency departments and for the optimal allocation of healthcare resources. Methods: This prospective study included 84 patients aged over 18 years who presented to the emergency department on 23 December 2020, with suspected SARS-CoV-2 infection. Initially, 100 patients were evaluated, and 16 were excluded based on predefined exclusion criteria. The mean age of the participants was 53.65 ± 13.62 years, and 39 (46.4%) were women. Results: At admission, the mean signal peptide, CUB domain, EGF (SCUBE-1) level among SARS-CoV-2 patients was 0.16 ± 0.08 ng/mL. There was no significant difference in SCUBE-1 levels between patient and control groups (n = 59 vs. 25), but levels differed significantly between hospitalized and home-treated patients (n = 37 vs. 22; p = 0.001). Neutrophil count (p = 0.001) and NLR (p = 0.010) were higher in patients than controls and also higher in hospitalized than home-treated patients (p = 0.003 and p = 0.015). ROC analysis revealed that SCUBE-1 predicted hospitalization with 84.6% sensitivity and 88.9% specificity. A positive correlation was observed between SCUBE-1 levels and length of hospital stay (p = 0.007, r = 0.554), with a median stay of 9.0 (5.0–11.0) days. Conclusions: SCUBE-1 levels were significantly associated with disease severity in SARS-CoV-2 patients and may serve as a promising biomarker to support clinical decision-making for hospitalization versus home-based management.