Since December 2019, the coronavirus disease (COVID-19) pandemic has catapulted the world into a marked health crisis, with over 29 million cases and >930,000 deaths. To better detect affected individuals at an early stage and stop disease progression to an advanced stage, several studies have been conducted to identify the clinical, biological, and radiological characteristics of COVID-19. This study aimed to enrich the literature by critically analyzing the clinical and biological characteristics of 134 patients from the North African Mediterranean region, including numerous genetic, epigenetic, and environmental factors that may influence disease evolution. This single-center retrospective study included all patients older than 18 years confirmed to have COVID-19 and hospitalized at the Cheikh Khalifa University Hospital affiliated with Mohammed VI University of Health Sciences, Casablanca, Morocco. Clinical, demographic, and biological data were analyzed in a cohort of severe and non-severe patients. Univariate analysis was performed to identify factors predictive of severity. There were 134 patients: the median age was 53 years, and 54.5% were male. Of these, 89 had mild to moderate disease; 45 had severe to critical disease, of which 14 died and 31 survived. Advanced age, presence of comorbidities, male sex, and infection in ethnic or family groups were risk factors for progression to severe disease. The presence of abnormalities in the following parameters were strongly associated with progression to severe disease: white blood cells (WBC), neutrophils, lymphocytes, C-reactive protein (CRP), procalcitonin, D-dimers, lactate dehydrogenase (LDH), ferritin, creatinine, aspartate aminotransferase (ASAT), and alanine aminotransferase (ALAT) during both admission and hospitalization. Based on these results and an extensive literature review, we recommend that clinicians closely monitor the biological parameters identified herein and perform immunological and genetic studies.