Late blight, caused by Phytophthora infestans (Mont.) de Bary, is the most devastating disease causing colossal yield losses in potato globally. With the goal of identifying resistant potato genotypes and understanding the underlying mechanisms, nine potato genotypes comprising of wild species Solanum chacoense (AC1, AC2), Solanum sparsipilum (AC3, AC4, AC5) and Solanum spegzinii (AC6) and three potato cultivars (Kufri Jyoti [KJ], Kufri Chandramuki [KC] and Kufri Girdhari [KG]), were evaluated for their response to late blight in field, in vitro detached leaf assays and assessed by biochemical analyses. The study identified genotypes, AC1, of Solanum chacoense and AC4 of Solanum sparsipilum, and cultivar, Kufri Girdhari as highly resistant, and genotype AC6, of Solanum spegzinii as the most susceptible genotype in this study. At field level, resistant genotypes AC4 and AC1 exhibited a novel mechanism of shedding infected leaves with a concomitant up-regulation of a systemic immune response. At the cellular level, all the potato genotypes exhibited a generalized response to infection with increase in peroxidase activity and calcium- dependent protein kinase accumulation. However, the resistant genotypes exhibited robust hydrogen peroxide production, cell death and callose deposition at the site of infection, thus arresting the progression of disease. With the initial infection, AC4 and AC1 showed significant induction of peroxidase and superoxide dismutase (SOD) enzyme activities and accumulation of phenolics and flavonoids, while resistant cultivar KG, exhibited relatively high basal SOD activity. All the three resistant genotypes exhibited prolonged heightened SOD activity even towards the end of the cropping season. The study implicates hypersensitive response as paramount in resistance of potato species against late blight. The popular and susceptible cultivar Kufri Jyoti, which was introduced initially as a resistant cultivar, was found to have some of the resistance mechanisms in place, however, showed subdued hypersensitive response.