Linum album is a well-known rich source of anticancer compounds, i.e., podophyllotoxin (PTOX) and other lignans, which play an important role in the plant defensive system. In the present study, the RNA-Seq data of flax (L. usitatissimum) under aluminum toxicity, zinc and K+ deficiency, drought stress, ABA, and Fusarium treatments were analyzed to identify common DEGs and then examined in L. album, using HPLC and qRT-PCR. Commonly DEGs analysis identified EP3 with a significant increase in all stresses. The highest expression increase was found for laccase )LAC11(, lactoperoxidase )POD(, 4-coumarate-CoA ligase )4CL(, and secoisolariciresinol (SECO) dehydrogenase )SDH(. A quantitative expression showed that the SDH gene had an increasing trend in L. album root and its expression trend was different in the plant shoot. The gene expressions of deoxyPTOX synthase (2-ODD), excluding drought stress, and 5'-desmethyl-yatein O-methyltransferase (OMT1) revealed a rising trend. HPLC analysis confirmed the results of gene expression. SECO content increased under drought stress, and 6-metoxyPTOX content was more than PTOX in both tissues. Identified modifications of critical genes related to PTOX biosynthesis in response to multiple stresses can provide a baseline for improving PTOX content.