Potato (Solanum tuberosum L) is affected by several viral pathogens with the most economically damaging being potato virus Y (PVY). At least nine biologically distinct variants of PVY are known to attack potato, with necrotic types named PVYNTN and PVYN-Wi being the most recent additions to the list. So far, the molecular plant-virus interactions underlying this pathogenicity are not fully understood. In this study, gas chromatography coupled with mass spectroscopy (GC–MS) was used for an untargeted investigation of the changes in leaf metabolomes of PVY-resistant cultivar Premier Russet, and a susceptible cultivar, Russet Burbank, following inoculation with three PVY strains, PVYNTN, PVYN-Wi, and PVYO. Analysis of the resulting GC–MS spectra with the online software Metaboanalyst (version 5.0) uncovered several common and strain-specific metabolites that are induced by PVY inoculation. In Premier Russet, the major overlap in differential accumulation was found between PVYN-Wi and PVYO. However, the 14 significant pathways occurred solely due to PVYN-Wi. In contrast, the main overlap in differential metabolite profiles and pathways in Russet Burbank was between PVYNTN and PVYO. Overall, limited overlap was observed between PVYNTN and PVYN-Wi. As a result, PVYN-Wi-induced necrosis may be mechanistically distinguishable from that of PVYNTN. Furthermore, 10 common and seven cultivar-specific metabolites as potential indicators of PVY infection and susceptibility/resistance were identified by using PLS-DA and ANOVA. In Russet Burbank, glucose-6-phosphate and fructose-6-phosphate were particularly affected by strain–time interaction. This highlights the relevance of the regulation of carbohydrate metabolism for defense against PVY. Some strain- and cultivar-dependent metabolite changes were also observed, reflecting the known genetic resistance–susceptibility dichotomy between the two cultivars. Consequently, engineering broad-spectrum resistance may be the most effective breeding strategy for managing these necrotic strains of PVY.