Liver cirrhosis causes physiological and pharmacokinetic alterations that complicate antihypertensive therapy, in the presence of portal and arterial hypertension. This study evaluated the efficacy and safety of PBPK-guided dosing of carvedilol and nebivolol in cirrhotic patients. First, PBPK models were validated using clinical pharmacokinetic data from healthy volunteers and optimized for cirrhosis, then applied to simulate untested cirrhotic populations and estimate unbound plasma exposure across disease stages. Second, a prospective, open-label, parallel randomized pilot study enrolled 44 cirrhotic patients (Child-Pugh; CP-A or B) with arterial hypertension, who received PBPK-guided doses of carvedilol or nebivolol, with 3 months of follow-up including monthly monitoring of adverse events, blood pressure, heart rate, portal hemodynamics by Doppler ultrasound, and laboratory safety parameters. The model predicted dose reductions of carvedilol 25 mg once daily and nebivolol 10 mg once daily to 11.26 mg and 4.98 mg in mild cirrhosis, 5.52 mg and 2.98 mg in moderate cirrhosis, and 1.99 mg and 1.23 mg in severe cirrhosis. Following administration of doses as close as possible to the PBPK-guided doses in CP A and B, both agents were well tolerated, effectively reducing blood pressure and heart rate without significant changes in hepatic and renal parameters. Portal hemodynamics and platelet count improved in both groups, with carvedilol showing greater effects; adverse events were mild and more frequent with carvedilol. While both drugs controlled blood pressure, carvedilol improved portal hemodynamics more. PBPK-guided dosing addressed pharmacokinetic changes, but pharmacodynamic differences between CP-A and CP-B persisted due to disease progression.