Fusarium wilt is a significant problem restricting the growth of the lily industry. However, Lilium regale Wilson is a valuable germplasm resource because of its Fusarium Wilt resistance. In this study, six endo-β-1,4-glucanase genes (Cel1-Cel6) in L. regale were identified among the differentially expressed genes reveled by omics data for L. regale infected Fusarium osysporum, which causes Fusarium wilt. Interestingly, the abundance of a few proteins and the expression of endo-β-1,4-glucanase genes, including LrCel1, decreased in L. regale roots infected with F. oxysporum. Thus, the function of LrCel1 in the incompatible interaction between L. regale and F. oxysporum was analyzed. LrCel1 expression was inhibited by F. oxysporum and salicylic acid (SA). Additionally, the subcellular localization of LrCel1 revealed it was a cell membrane protein. The ectopic expression of LrCel1 increased of susceptibility of tobacco to F. oxysporum because of the associated increase in cellulase activity, which, hindered the production of cellulose, callose, and lignin. Moreover, LrCel1 overexpression inhibited the accumulation of SA and jasmonic acid (JA), resulting in the down-regulated expression of genes associated with SA/JA signaling pathways. Conversely, introducing an RNAi vector targeting LrCel1 into L. regale enhanced the resistance to F. oxysporum, likely because of an increase in the synthesis of cellulose, callose, and lignin as well as a decrease in the expression of JA/SA signaling pathway genes. In addition, LrCel1 promoter activity was suppressed by F. oxysporum and Fusarium solani as well as SA. Furthermore, a positive regulator of Fusarium wilt resistance, LrWRKY11, negatively regulated LrCel1 promoter activity. The study findings have elucidated the intricate regulatory network of WRKY transcription factor and SA/JA signaling pathways to inhibit the cellulase activity of endo-β-1,4-glucanase in L. regale, thereby conferring resistance to Fusarium wilt.