Oral administration of drug products is a strict requirement in many medical indications. Therefore, bioavailability prediction models are of high importance for prioritization of compound candidates in the drug discovery process. However, oral exposure and bioavailability are difficult to predict, as they are the result of various highly complex factors and/or processes influenced by the physicochemical properties of a compound, such as solubility, lipophilicity, or charge state, as well as by interactions with the organism, for instance, metabolism or membrane permeation. In this study, we assess whether it is possible to predict intravenous (iv) or oral drug exposure and oral bioavailability in rats. As input parameters, we use (i) six experimentally determined in vitro and physicochemical endpoints, namely, membrane permeation, free fraction, metabolic stability, solubility, pKa value, and lipophilicity; (ii) the outputs of six in silico absorption, distribution, metabolism, and excretion models trained on the same endpoints, or (iii) the chemical structure encoded as fingerprints or simplified molecular input line entry system strings. The underlying data set for the models is an unprecedented collection of almost 1900 data points with high-quality in vivo experiments performed in rats. We find that drug exposure after iv administration can be predicted similarly well using hybrid models with in vitro- or in silico-predicted endpoints as inputs, with fold change errors (FCE) of 2.28 and 2.08, respectively. The FCEs for exposure after oral administration are higher, and here, the prediction from in vitro inputs performs significantly better in comparison to in silico-based models with FCEs of 3.49 and 2.40, respectively, most probably reflecting the higher complexity of oral bioavailability. Simplifying the prediction task to a binary alert for low oral bioavailability, based only on chemical structure, we achieve accuracy and precision close to 70%.