Abstract: Natural products exhibit complex in vivo behaviors governed by dynamic exposure, multi-target interactions, and inter-organ crosstalk, which conventional preclinical models poorly capture. Organ-on-a-chip (OOC) technologies provide human-relevant in vitro platforms that integrate physiological flow, tissue architecture, and multicellular interactions. This review systematically summarizes recent advances in gut, liver, and multi-organ chip systems for investigating key processes underlying the absorption, metabolism, and systemic exposure of natural products. We further highlight the application of disease-specific OOC models in evaluating pharmacological responses under pathophysiological conditions and assessing organ-specific and immune-related safety risks of natural products. Finally, we discuss current challenges and future directions for OOC-based natural product research, including prioritizing functional biomarker-based standardization, incorporating patient-specific cell sources, engineering systems tailored to the complexity of natural products, and exploring emerging research frontiers, all anchored in mechanistic in vitro-in vivo extrapolation (IVIVE) and quantitative systems pharmacology frameworks toward predictive Digital Twins. Collectively, OOC platforms provide a systematic and translational framework for studying the complex pharmacokinetics and biological effects of natural products.