Concomitant food intake can diminish oral absorption of drugs with limited permeability and an absorption window in the proximal intestine, due to viscosity-mediated decrease in dosage form disintegration time and drug dissolution rate. Three poorly-permeable drugs (atenolol, metformin hydrochloride, and furosemide) exhibiting negative food effect, and one highly-soluble and highly-permeable (metoprolol tartrate), serving as a negative control, were selected for the study. In vitro and in silico tools were used to evaluate the influence of media viscosity on drug bioperformance under fasted and fed conditions. The obtained results demonstrated that increased medium viscosity in the presence of food is one of the key factors limiting oral absorption of drugs with limited permeability and absorption restricted to the upper parts of the intestine, while having negligible effect on pharmacokinetic profile of drugs with pH- and site-independent absorption. Dissolution medium pH 4.6 with the addition of hydroxypropyl methylcellulose was suggested to simulate postprandial gastric conditions for drugs whose solubility under these conditions is not the limiting factor for drug absorption. In addition, drug formulation was found to be an interfering factor in relation to the impact of medium viscosity on the rate and extent of drug absorption.