Resistance to late blight is highly complex and quantitative in nature but has proven difficult to harness due to poor understanding of its molecular and biochemical mechanisms. Secondary cell wall (SCW) biosynthesis is a critical process in late blight resistance, regulated by an array of transcription factors (TF). In the present study, metabolo-transcriptomics approaches were used to functionally characterize that the upregulated StNAC43 and StMYB8 in potato genotypes were linked to SCW biosynthetic phenylpropanoid metabolites produced in high fold change following Phytophthora infestans infection. The promoter analysis of StNAC43 revealed the presence of ethylene responsive element (ERE), which is the proposed binding site for ethylene responsive factor, ERF3. Sequencing of the ERF3 revealed a frameshift mutation in the susceptible potato genotype. Simultaneous induction of both the ERF3 and StNAC43, following pathogen invasion, enables functioning of the latter to interact with the ERE present in the resistant StNAC43 promoter region. Further, the StNAC43 binds to the secondary NAC binding element in StMYB8 promoter and activates StMYB8 TF. A luciferase transient expression assay elucidated a direct regulatory role of the StMYB8 on SCW biosynthetic genes, by binding to promoters of downstream genes: HCT, PHT, CHS, and flavanone 3-hydroxylase (F3H). Silencing of StNAC43 and StMYB8 affected the late blight resistance by significantly increasing pathogen biomass and decreasing the amounts of hydroxycinnamic acid amides (HCAAs) and flavonoid glycosides. The StNAC43 and StMYB8 TFs are positive activators of SCW biosynthetic genes, which deposit resistance-related metabolites to reinforce SCW and improve resistance against late blight.