Plant-based therapeutic agents have garnered increasing attention as potential sources of novel drug candidates and complementary medicines, yet their clinical translation remains hindered by significant pharmacokinetic challenges and unpredictable bioavailability profiles. The complexity of phytochemical mixtures, variability in plant material composition, and inherent physicochemical properties such as poor aqueous solubility and extensive metabolism contribute to suboptimal systemic exposure following oral administration. This article examines the pharmacokinetic principles governing the absorption, distribution, metabolism, and excretion of plant-derived drugs, with particular emphasis on factors that influence bioavailability including first-pass hepatic metabolism, efflux transporter activity, and physicochemical characteristics. Critical evaluation of formulation strategies designed to enhance systemic availability, such as nanoparticle-based delivery systems, liposomal encapsulation, solid dispersions, and structural modifications, is presented alongside preclinical and clinical evidence demonstrating their efficacy. The interplay between herb-drug interactions, safety considerations, and the necessity for rigorous standardization in phytopharmaceutical development is discussed within the context of regulatory requirements. Emerging technologies including precision dosing approaches, pharmacokinetic modeling, and personalized phytotherapy represent promising avenues for optimizing therapeutic outcomes. This comprehensive review synthesizes current knowledge on the pharmacokinetic challenges inherent to plant-based drugs and proposes future directions for advancing formulation science and clinical application of phytopharmaceuticals in evidence-based medicine.