Fimasartan is a novel angiotensin II receptor blocker. Our aims were to characterize the time-course of the antihypertensive activity of fimasartan via a new population pharmacokinetic/pharmacodynamic model and to define its optimal dose range. We simultaneously modelled all fimasartan plasma concentrations and 24-h ambulatory blood pressure monitoring (ABPM) data from 39 patients with essential hypertension and 56 healthy volunteers. Patients received placebo, 20, 60, or 180 mg fimasartan every 24 h for 28 days and healthy volunteers received placebo or 20 to 480 mg as a single oral dose or as seven doses every 24 h. External validation was performed using data on 560 patients from four phase II or III studies. One turnover model each was used to describe diastolic and systolic blood pressure. The input rates into these compartments followed a circadian rhythm and were inhibited by fimasartan. The average predicted (observed) diastolic blood pressure over 24-h in patients decreased by 10.1 ± 7.5 (12.6 ± 9.2; mean ± SD) mmHg for 20 mg, 14.2 ± 7.0 (15.1 ± 9.3) mmHg for 60 mg, and 15.9 ± 6.8 (11.5 ± 9.9) mmHg for 180 mg daily relative to placebo. The model explained the saturation of antihypertensive activity by counter-regulation at high fimasartan concentrations. Drug effect was maximal at approximately 23 ng/mL fimasartan for diastolic and 12 ng/mL for systolic blood pressure. The proposed mechanism-based population model characterized the circadian rhythm of ABPM data and the antihypertensive effect of fimasartan. After internal and external model validation, 30 to 60 mg oral fimasartan given once daily was predicted as optimal dose range.