The rhizome of Ligusticum chuanxiong Hort. is a well-known traditional Chinese medicinal herb that is widely used to treat various vascular diseases. The aims of this study were to identify and compare the metabolites in rats after the oral administration of the essential oil of Ligusticum chuanxiong Hort. or its major constituent ligustilide monomer, and to explore the differences in the metabolism of the main active constituent monomer and the active constituent group. High-performance liquid chromatography with diode array detection was used to analyze the metabolites in the urine, feces, and bile of rats dosed with the essential oil or ligustilide. We observed clear differences in the metabolism of the essential oil and ligustilide. The other chemical constituents in the essential oil influenced the metabolism of the main active constituent monomer. Four metabolites in urine were separated, purified, and identified as 6,7-dihydro-6,7-dihydroxyligustilide (M1), 3,5-dihydroxy-3-butylphthalide (M2), 6,7-dihydro-6-hydroxy-7-sulfmethylligustilide (M3), and 5-hydroxy-3-butylidenephthalide (M4) by FT-ICR-MS and 1H-NMR. M2 and M3 are novel metabolites. Based on the profiles of these metabolites, the pathway of ligustilide metabolism in rats is proposed.