Background/Objectives: The external oblique intercostal (EOI) plane block shows promise for postoperative analgesia after open liver surgery. Pharmacokinetic profiles of ropivacaine after EOI plane block remain unclear. Meanwhile the pharmacokinetic data informs safety assessment, guides post-block monitoring duration, and predicts blockade duration. This study aimed to characterize ropivacaine pharmacokinetics and propose a safe dosing regimen. Methods: In this prospective study, patients undergoing open liver surgery received a unilateral single-shot ultrasound-guided EOI plane block with 30 mL of 0.375% ropivacaine. Plasma ropivacaine concentrations were measured to define pharmacokinetics, identify influencing factors, and develop physiology-based pharmacokinetic (PBPK) models for dose optimization. Results: Twenty-eight patients (Child-Pugh A, ≤3 liver segments resected) were included. Peak plasma ropivacaine concentration occurred at 10 min and remained below the toxic threshold in all patients. No adverse events were observed. Demographic and surgical factors did not significantly affect pharmacokinetics. The PBPK model-predicted safe doses of ropivacaine were comparable across age groups and relatively high. Conclusions: A single-shot EOI plane block with ropivacaine is safe for patients undergoing open liver surgery (Child-Pugh A) with limited resection (≤3 segments). This study provides critical pharmacokinetic data and validated PBPK model, guiding safe dosing to reduce toxicity risks.