<p>Accurate prediction of oral drug absorption is essential for anticipating variability in bioavailability and guiding clinical development. Physiological factors, such as gastric pH, gastric emptying, and intestinal transit time, influenced by food intake and acid-reducing agents (ARAs), play critical roles in the dissolution and absorption of drugs with pH-dependent solubility. Intestinal transporters and metabolizing enzymes also affect systemic exposure by regulating drug absorption, metabolism, and excretion in the intestine. Species differences in gastrointestinal physiology, including pH profiles, transporter expression, and motility patterns, present challenges when translating nonclinical data to humans. Physiologically based pharmacokinetic (PBPK) modeling offers a mechanistic framework to address these variations by integrating drug- and species-specific parameters. By calibrating <i>in vitro</i> and <i>in vivo</i> data, PBPK models can simulate human gastrointestinal conditions and more accurately predict oral absorption dynamics, enhancing translational relevance. These models facilitate early evaluation of food and ARA impacts, transporter-related absorption variabilities, and drug-drug interactions (DDIs), supporting the rational development of formulation and dose selection. Verifying model performance in nonclinical species, commonly in dogs, can further enhance confidence in human predictions. This review highlights drug- and species-specific factors and illustrates how PBPK modeling can address uncertainties regarding drug absorption in humans using nonclinical <i>in vitro</i> and <i>in vivo</i> data. Despite challenges such as parameter uncertainty and interspecies differences, PBPK modeling remains a valuable tool for estimating drug exposure and informing biopharmaceutical and clinical pharmacology strategies.</p> Graphical Abstract <p></p>