Bupleurum and Paeonia are common compatibilities for the treatment of depression, most of which are used in classical prescriptions. The main active ingredients saikosaponin A (SSA) and paeoniflorin (PF) have significant therapeutic effects on poststroke depression (PSD). However, the pharmacokinetic (PK) behavior based on the combination of the two components has not been reported in rats. The aim of this study was to compare the pharmacokinetic characteristics of combined administration of SSA and PF in normal and PSD rats. Plasma samples were collected after SSA and PF were injected into the rat tail vein, and plasma pretreatments were analyzed by HPLC. Based on the concentration levels of SSA and PF in plasma, Drug and Statistics 3.2.6 (DAS 3.2.6) software was used to establish the blood drug concentration model. PK data showed that compared with the normal rats, the values of related parameters t1/2α, AUC(0−t), AUC(0-∞) were decreased in diseased rats, while the values of CL1 was increased. These findings suggest that PSD can significantly affect the PK parameters of SSA-PF. This study established a PK model to explore the time-effect relationship, in order to provide experimental and theoretical support for clinical application.