Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUC_IBRU) instead of trough concentration (C_min,ss) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy (LSS) to estimate AUC_IBRU associated with Bayesian estimation. The actual AUC_IBRU of 85 patients was determined by the Bayesian analysis of the full pharmacokinetic profile of ibrutinib concentrations (pre-dose T0 and 0.5, 1, 2, 4 and 6 h post-dose) and experimental AUC_IBRU were derived considering combinations of one to four sampling times. The T0–1–2–4 design was the most accurate LSS (root-mean-square error RMSE = 11.0%), and three-point strategies removing the 1 h or 2 h points (RMSE = 22.7% and 14.5%, respectively) also showed good accuracy. The correlation between the actual AUC_IBRU and C_min,ss was poor (r² = 0.25). The joint analysis of dihydrodiol-ibrutinib metabolite concentrations did not improve the predictive performance of AUC_IBRU. These results were confirmed in a prospective validation cohort (n = 27 patients). At least three samples, within the pre-dose and 4 h post-dose period, are necessary to estimate ibrutinib exposure accurately.