Shengmaisan (SMS) is a traditional Chinese medicine prescription widely used for the treatment of cardiovascular diseases in Asia. Its lignans are major components responsible for therapeutic action. A rapid and specific UPLC-Q-TOF/MS has been developed and validated for simultaneous quantification of the five main bioactive components, i.e. schisandrin, schisandrol B, schisantherin A, deoxyschisandrin, and schisandrin B, in rat plasma after oral administration of SMS. All calibration curves showed excellent linearity within the test ranges. Validation proved the repeatability of the method was good and recovery was satisfactory. The separation of these compounds was carried out on a Waters ACQUITY HSS T3 column (2.1 × 100 mm, 1.8 μm) by linear gradient elution using a mobile phase consisting of 0.01% formic acid in water and ACN containing 0.01% formic acid. In this work, plasma pharmacokinetic characteristics of lignans components after oral administration SMS were investigated using UPLC-Q-TOF/MS method. MS was performed on a Waters Micromass high-definition technology with an ESI source. Data were analyzed and estimated by compartmental methods and pharmacokinetic parameters calculated using WinNonlin Professional version 6.1. Results demonstrated that the proposed UPLC-Q-TOF/MS method was successfully applied to pharmacokinetic study of all components in rat plasma after oral administration of the SMS.