Plant protection based on novel alternative strategies is a major concern in agriculture to sustain pest management. The marc extract of red grape cultivars reveals plant defence inducer properties. Treatment with grape marc extract efficiently induced hypersensitive reaction-like lesions with cell death evidenced by Evans Blue staining of tobacco leaves. Examination of the infiltration zone and the surrounding areas under UV light revealed the accumulation of autofluorescent compounds. Both leaf infiltration and a foliar spray of the red grape extract on tobacco leaves induced defence gene expression. The PR1 and PR2 target genes were upregulated locally and systemically in tobacco plants following grape marc extract treatment. The grape extract elicited an array of plant defence responses making this natural compound a potential phytosanitary product with a challenging issue and a rather attractive option for sustainable agriculture and environmentally friendly practices.