Liver biochemical abnormalities have been reported in nearly half of patients with SARS-CoV-2 infection. The study aimed to determine the prevalence of altered liver biomarkers (alanine transaminase—ALT, aspartate aminotransferase—AST, lactate dehydrogenase—LDH, gamma-glutamyl transferase—GGT, and albumin) in COVID-19 patients with a moderately severe clinical picture on hospital admission, and to assess the presence of altered liver-related biomarkers in the absence of a severe clinical presentation. Research material consisted of medical histories of patients with a moderately severe clinical picture of COVID-19 who were hospitalized at the Clinic for Infectious Diseases of the University Clinical Centre Niš. The study included 655 patients (425 male and 230 female) who were divided into three groups: patients without comorbidities (NC), patients with arterial hypertension (HTA), and patients previously diagnosed with diabetes mellitus (DM). Additionally, within each research group, patients were divided into three age subgroups: patients aged 20-40 years, 40-60 years, and over 60 years. AST, ALT, and LDH showed statistically significant differences across the defined groups, while GGT did not. Logistic regression confirmed increased odds for elevated AST and LDH values in all older and comorbid groups, with the most pronounced effects for LDH. For ALT, significantly increased odds were observed among patients with HTA (40–60 years) and DM (40–60 years). The most pronounced changes were observed in elderly patients and those with hypertension and diabetes, with LDH emerging as the most sensitive, although non-specific biomarker, likely reflecting systemic inflammation and disease severity in addition to possible hepatic involvement.