Umbelliferone (7-hydroxycoumarin) is a naturally occurring coumarin widely distributed in higher plants and noted for its diverse pharmacological benefits. Despite its therapeutic potential, little is known about its quantitative pharmacokinetics owing to extensive phase II metabolism and low systemic exposure after oral administration. To address this gap, we developed whole-body physiologically based pharmacokinetic (PBPK) models in rats and humans, integrating experimental data on solubility, protein binding, blood distribution, intestinal permeability, and tissue-dependent metabolism. The gut model was constructed using the Q_Gut model to better describe route-specific intestinal extraction. Model verification showed that simulated rat concentration–time profiles were consistent with in vivo findings across intravenous and oral dosing, with prediction errors within 2-fold. Human PBPK simulations predicted dose-proportional kinetics, low oral bioavailability (9.5%), and identified absorption fraction, protein binding, and hepatic/intestinal clearance as sensitive determinants of systemic disposition. These results highlight the utility of PBPK modeling to mechanistically interpret the complex disposition of natural products and to inform the rational design of phytochemical-based functional foods and drug-natural product interaction risk assessment.