The understanding of the molecular defensive mechanism ofEchinacea purpurea(L.) Moench against polycyclic aromatic hydrocarbon (PAH) contamination plays a key role in the further improvement of phytoremediation efficiency. Here, the responses ofE. purpureato a defined mixture of phenanthrene (PHE) and pyrene (PYR) at different concentrations or a natural mixture from an oilfield site with a history of several decades were studied based on transcriptomics sequencing and widely targeted metabolomics approaches. The results showed that upon 60-day PAH exposure, the growth ofE. purpureain terms of biomass (p< 0.01) and leaf area per plant (p< 0.05) was negatively correlated with total PAH concentration and significantly reduced at high PAH level. The majority of genes were switched on and metabolites were accumulated after exposure to PHE + PYR, but a larger set of genes (3964) or metabolites (208) showed a response to a natural PAH mixture inE. purpurea. The expression of genes involved in the pathways, such as chlorophyll cycle and degradation, circadian rhythm, jasmonic acid signaling, and starch and sucrose metabolism, was remarkably regulated, enhancing the ability ofE. purpureato adapt to PAH exposure. Tightly associated with transcriptional regulation, metabolites mainly including sugars and secondary metabolites, especially those produced via the phenylpropanoid pathway, such as coumarins, flavonoids, and their derivatives, were increased to fortify the adaptation ofE. purpureato PAH contamination. These results suggest thatE. purpureahas a positive defense mechanism against PAHs, which opens new avenues for the research of phytoremediation mechanism and improvement of phytoremediation efficiency via a mechanism-based strategy.