The intrinsic metabolic clearance rate (Clint) and the fraction of the chemical unbound in plasma (fup) serve as important parameters for high-throughput toxicokinetic (TK) models, but experimental data are limited for many chemicals. Open-source quantitative structure-activity relationship (QSAR) models for both parameters were developed to offer reliable in silico predictions for a diverse set of chemicals regulated under the U.S. law, including pharmaceuticals, pesticides, and industrial chemicals. As a case study to demonstrate their utility, model predictions served as inputs to the TK component of a risk-based prioritization approach based on bioactivity/exposure ratios (BERs), in which a BER < 1 indicates that exposures are predicted to exceed a biological activity threshold. When applied to a subset of the Tox21 screening library (6484 chemicals), we found that the proportion of chemicals with BER <1 was similar using either in silico (1133/6484; 17.5%) or in vitro (148/848; 17.5%) parameters. Further, when considering only the chemicals in the Tox21 set with in vitro data, there was a high concordance of chemicals classified with either BER <1 or >1 using either in silico or in vitro parameters (767/848, 90.4%). Thus, the presented QSARs may be suitable for prioritizing the risk posed by many chemicals for which measured in vitro TK data are lacking.