Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease in Western countries, has been identified as a possible risk factor for COVID-19 severity. However, the immunological mechanisms by which NAFLD exacerbates COVID-19 remain unknown. Transforming growth factor-beta 1 (TGF-β1) has an important immunomodulatory and pro-fibrotic role, which has already been described in NAFLD. However, the role of TGF-β1 in COVID-19 remains unclear, and could also be the pathophysiology link between these two conditions. The aim of this case–control study was to analyze the expression of TGF-β1 in COVID-19 patients depending on the presence of NAFLD and COVID-19 severity. Serum TGF-β1 concentrations were measured in 60 hospitalized COVID-19 patients (30 with NAFLD). NAFLD was associated with higher serum TGF-β1 concentrations that increased with disease severity. Admission TGF-β1 concentrations showed good discriminative accuracy in predicting the development of critical disease and COVID-19 complications (need for advanced respiratory support, ICU admission, time to recovery, development of nosocomial infections and mortality). In conclusion, TGF-β1 could be an efficient biomarker for predicting COVID-19 severity and adverse outcomes in patients with NAFLD.