Fusarium crown rot (FCR), mainly caused byFusarium pseudograminearum, not only seriously threatens the yield and quality of wheat, but also endangers the health and safety of humans and livestock.Piriformospora indicais a root endophytic fungus that colonizes plant roots extensively and can effectively promote plant growth and improve plant resistance to biotic and abiotic stresses. In this study, the mechanism of FCR resistance mediated byP. indicain wheat was revealed from the phenylpropanoid metabolic pathway. The results showed that the colonization ofP. indicasignificantly reduced the progression of wheat disease, the amount ofF. pseudograminearumcolonization, and the content of deoxynivalenol (DON) in wheat roots. RNA-seq suggested thatP. indicacolonization could reduce the number of differentially expressed genes (DEGs) in the transcriptome caused byF. pseudograminearuminfection. The DEGs induced by the colonization ofP. indicawere partially enriched in phenylpropanoid biosynthesis. Transcriptome sequencing and qPCR indicated that the colonization ofP. indicaup-regulated the expression of genes involved in the phenylpropanoid biosynthesis pathway. The metabolome analysis indicated that the colonization ofP. indicaincreased the metabolites’ accumulation in the phenylpropanoid biosynthesis. Consistent with transcriptome and metabolomic analysis, microscopic observations showed enhanced lignin accumulation in the roots of the Piri and Piri+Fp lines, most likely contributing to the arrested infection byF. pseudograminearum.These results suggested thatP. indicaincreased resistance toF. pseudograminearumin wheat by inducing the phenylpropanoid pathway.