Acetaminophen is a widely used oral analgesic and antipyretic medication; however, quality control parameters may differ across various brands. The aim of the present study was to evaluate and compare critical quality attributes, including in-vitro dissolution characteristics, of five acetaminophen tablet brands (labeled A–E) from the Saudi market and determine their pharmaceutical equivalence. All brands were tested for conformity with the United States Pharmacopoeia (USP) standards, through evaluation of weight variation, hardness, friability, disintegration, and dissolution. Dissolution profiles were compared using model-dependent and independent approaches relative to the innovator brand A (Panadol). All tested brands passed the weight variation and friability tests with deviations of less than 5% from the average weight and less than 1% weight loss, respectively, with the exception of brand C showing relatively higher friability (1.13%). All brands displayed variable disintegration times; however, all were compliant with USP specifications. All studied tablets released less than 80% of the drug within 30 minutes; however, brands B and C had lower drug release rates, area under the curve (AUC), and dissolution efficiency (DE) compared with the innovator. Brand E, on the other hand, had a higher drug release rate, AUC, DE, and mean dissolution time (MDT), and thus was pharmaceutically inequivalent to the innovator. All tested brands exhibited a non swellable matrix diffusion-controlled dissolution as assessed by the Korsmeyer-Peppas model of drug-release kinetics. In conclusion, all acetaminophen brands were able to pass USP specifications to justify interchangeability. Minor variations in in-vitro dissolution characteristics could reflect inherent manufacturing compounding differences.