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The depression model was induced by exposure to chronic unpredictable mild stress.Pharmacokinetics of 7 bioactive components in Baihe Zhimu decoction were determined.The AUC0-t, AUC0-∞, CL and Cmax were significantly different.Factors might result in the differences were proposed.A simple and rapid liquid chromatography–tandem mass spectrometry method was firstly developed for simultaneous quantification of neomangiferin, mangiferin, regaloside A, regaloside I, timosaponin BII, anemarsaponin E and timosaponin AIII in rat plasma after oral administration of Baihe Zhimu decoction, which plays an important role for the treatment of depression. The plasma samples were pretreated by a one-step direct protein precipitation with methanol. Separation of the seven components and scutellarin (IS) from endogenous components with high selectivity and sensitivity (LLOQ, 0.1–1.0 ng/mL) was achieved within 10 min using Poroshell 120 EC-C18 column (150 mm × 3.0 mm, 2.7 μm). A gradient mobile phase consisting of acetonitrile and water (containing 5 mM ammonium acetate) was applied at a flow rate of 0.4 mL/min. Detection and measurement were performed on an AB Sciex QTRAP® 5500 mass spectrometer in multiple reactions monitoring mode. The intra- and inter-day precisions were all within 15% and the accuracies were in the range of −10.4% to 14.5%. The recovery ranged from 90.8 to 113.8%. The validated method was successfully applied to pharmacokinetic study of the seven components in normal and chronic unpredicted mild stress-induced depression model rats.