Caffeic acid-O-methyltransferase (COMT) is a crucial enzyme in the phenylpropanoid metabolic pathway, with significant roles in both the lignin and coumarin pathways. The function of COMT in plant disease resistance has been demonstrated in several species. Our research identified the potato COMT gene family on a genome-wide scale and StCOMT1 as a candidate gene for enhancing potato disease resistance under DON induction through phylogenetic analyses combined with previously identified metabolic differences and weighted gene co-expression network analysis (WGCNA) results. In order to better understand the function of StCOMT1, heterologous expression and overexpression assays were conducted. StCOMT1 is localized in chloroplasts and was found to catalyze the methylation of substrates to produce ferulic acid and melatonin in vitro. Physiological parameters showed that, compared with wild-type potato plants, StCOMT1-overexpressing plants infected with Fusarium sporotrichioides exhibited smaller lesion areas and lower reactive oxygen species (ROS) levels. High-performance liquid chromatography (HPLC) and RT-qPCR analyses revealed organ-specific accumulation of coumarin-related compounds and organ-specific expression of their corresponding genes in StCOMT1-overexpressing plants post-inoculation. The results indicate that StCOMT1 overexpression in potatoes enhanced resistance to F. sporotrichioides by enhancing reactive oxygen species clearance and promoting organ-specific accumulation of coumarin-related compounds.