Chrysin is a promising naturally occurring flavonoid mainly found in honey and propolis. Although chrysin’s biological activities have been demonstrated and the mechanism of actions has been determined using in vitro and in vivo models, results from the current clinical studies were largely negative. A potential reason for chrysin’s low efficacy in humans is poor oral bioavailability. In this paper, we reviewed the preclinical and clinical pharmacokinetics studies of chrysin and analyzed the mechanism of poor in vivo efficacy with emphasis on its bioavailability and ADME mechanism. Low aqueous solubility, rapid metabolism mediated by UGTs and SULT, efficient excretion through efflux transporters including BCRP and MRP2 are the major reasons causing poor systemic bioavailability for chrysin. However, because of efficient enterohepatic recycling facilitated by phase II metabolism and efflux, chrysin’s bioavailability in the low GI tract is high. Thus, chrysin can be ideal for treating diseases in the terminal ileum and colon (e.g., carcinoma, local infection) since it is localized in the lower GI tract with limited delivery to other organs.