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The current study aimed to evaluate the bioequivalence of a new generic combination of simvastatin and ezetimibe with the reference formulation. An open‐label, randomized, 3‐period, 3‐sequence, crossover study, including 60 healthy volunteers, was implemented. Participants received the test and reference formulation, each containing 20 mg of simvastatin and 10 mg of ezetimibe as a single‐dose tablet, separated by a minimum of 2‐week washout periods. Blood samples were collected for 20 time points from predose to 72 hours after the dose. The total ezetimibe assay was carried out using a validated liquid chromatography‐tandem mass spectrometry, while unconjugated ezetimibe, simvastatin, and simvastatin β‐hydroxy acid determination was done via a validated ultra‐performance liquid chromatography‐tandem mass spectrometry. Each assay was preceded by a liquid‐liquid extraction step. The pharmacokinetic parameters were derived using noncompartmental analysis and then compared between the reference and test formulations via a multivariate analysis of variance. No statistical difference was found in under the concentration‐time curve from time 0 to the last quantifiable concentration and maximum concentration of unconjugated ezetimibe, total ezetimibe, and simvastatin between the reference and test formulations. The 90% confidence intervals of unconjugated ezetimibe, total ezetimibe, and simvastatin natural log‐transformed under the concentration‐time curve from time 0 to the last quantifiable concentration, and maximum concentration were in the range of 80%‐125% as per the bioequivalence acceptance criteria. Therefore, the test formulation was bioequivalent to the reference formulation. [ABSTRACT FROM AUTHOR]