Cystic fibrosis (CF) is a multisystem disease in which liver involvement may progress to cirrhosis and portal hypertension. The introduction of CFTR modulator therapy has significantly improved the prognosis of patients with CF; however, the use of these agents in patients with decompensated liver cirrhosis remains limited due to the risk of drug-induced liver injury and the lack of clinical data. We present a clinical case of combination therapy with ivacaftor+tezacaftor+elexacaftor/ivacaftor in a 29-year-old patient with CF (F508del/F508del genotype), decompensated Child—Pugh C liver cirrhosis, and placement on the liver transplantation waiting list. During 6 months of therapy, stabilization of respiratory status, reduction in the severity of respiratory failure, and improvement in liver function parameters and nutritional status were observed. No clinically significant adverse events or signs of drug-induced liver injury were recorded. This clinical observation demonstrates the potential feasibility of CFTR modulator therapy in selected patients with severe CF-associated liver disease, provided that a multidisciplinary approach and careful clinical and laboratory monitoring are ensured.