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Background/Objectives: Charlson Comorbidity Index (CCI) is one of the most reliable indicators to assess the impact of multimorbidity on COVID-19-related outcomes. Moreover, the patient's clinical conditions are associated with SARS-CoV-2 outcomes. This study aimed to analyze the association between multimorbidity and COVID-19-related outcomes, evaluating whether the National Early Warning Score 2 (NEWS2) mediated these associations. Methods: Data were obtained through the platform "EPICLIN". We analyzed all patients who tested positive for COVID-19 after accessing the emergency department (ED) of San Luigi Gonzaga (Orbassano) and Molinette (Turin) hospitals from 1 March to 30 June 2020. Different outcomes were assessed: non-discharge from the ED, 30-day mortality, ICU admission/death among hospitalized patients, and length of hospitalization among surviving patients. Two subgroups of patients (<65 and 65+ years old) were analyzed using logistic regressions, Cox models, and mediation analyses. Results: There was a greater risk of not being discharged or dying among those who were younger and with CCI ≥ 2. Moreover, the higher the CCI, the longer the length of hospitalization. Considering older subjects, a greater CCI was associated with a higher risk of death. Regarding the mediation analyses, multimorbidity significantly impacted the hospitalization length and not being discharged in the younger population. Instead, in the older population, the NEWS2 played a mediation role. Conclusions: This research showed that multimorbidity is a risk factor for a worse prognosis of COVID-19. Moreover, there was a strong direct effect of CCI on not being discharged, and the NEWS2 was found to act as mediator in the association between multimorbidity and COVID-19-related outcomes. [ABSTRACT FROM AUTHOR]