Radix Bupleuri (RB), also named Chaihu in Chinese, is a commonly used herbal drug in traditional Chinese medicine (TCM), and the processing of RB with vinegar to prepare vinegar-baked Radix Bupleuri (VBRB) has a long history in the clinic of TCM. In the present study, GC-MS coupled with multivariate data analysis was applied to compare the volatile components between crude and two vinegar processed RBs. After vinegar baking, the oil yields were decreased significantly, and the chemical compositions were also changed greatly. The chemical changes included the disappearance or appearance, as well as the content increase or decrease of some volatile compounds. The oil yields of two different VBRBs showed no significant difference but differed markedly in their chemical compositions, suggesting that the type of vinegar exerted great impacts on the vinegar-baking process. Thus, the effect of different vinegars on processing should be further investigated to ensure the therapeutic effect and safety of VBRB in clinic.