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Abnormal liver function tests are frequently reported in patients with COVID-19. This study aimed to identify potential treatment-associated hepatocellular injury in COVID-19 patients by dynamically assessing circulating miR-122, a biomarker with high hepatic specificity and sensitivity. An exploratory approach was additionally used, given the limited evidence regarding factors influencing miR-122 expression in this setting. We performed a prospective cohort study including 96 adult participants enrolled at a tertiary hospital in Bucharest, Romania, between March 2022 and July 2023: 78 COVID-19 patients (57 with baseline and follow-up miR-122 assessment after 5 days of treatment and 21 with a single measurement) and 18 non-COVID-19 participants included for comparison. Plasma miR-122 levels were measured using quantitative polymerase chain reaction, normalized to U6 small nuclear RNA, and expressed as log₁₀(2^-ΔCt). No associations were observed between miR-122 expression and remdesivir administered for standard treatment durations (3-5 days) or other COVID-19-specific therapies. However, a duration-dependent relationship with remdesivir cannot be excluded. Moreover, therapeutic paracetamol use prior to presentation was positively associated with miR-122 expression at follow-up and remained significant after adjustment. Additionally, bivariate analyses revealed inverse correlations between baseline miR-122 and inflammatory biomarkers, with multivariable analysis showing an independent positive association with lymphocyte count.