Late Blight caused by Phytophthora infestans (Mont.) de Bary is the most destructive foliar disease causing 30% yield losses in the potato (Solanum tuberosum L.) crop globally. Wild potato genotypes AC1 and AC4, and potato cultivar Kufri Girdhari are highly resistant, whereas wild genotype AC6, and cultivars Kufri Chandramuki and Kufri Jyoti are susceptible to Late Blight. In the current study, the calli of these six potato genotypes were used to understand the mechanism of cellular resistance to Late Blight. Exposure to P. infestans or its elicitors significantly induced peroxidase (POX) and superoxide dismutase (SOD) activities, and induced accumulation of phenolics and flavonoids, indicating the capability of the calli cells to mount a defense response. The study is the first to report the extracellular secretion of defense enzymes, SOD and POX when cells encounter the pathogen, implicating a similar whole-plant phenomenon of enhanced defense in the apoplast. Interestingly, the calli of resistant genotypes showed poor survival upon exposure to pathogen or when grown on elicitor medium, while the susceptible genotypes showed better survival. The percentage of calli cells accumulating intracellular H2O2 was high in resistant genotypes, and directly correlated with the observed higher cell death. The study shows that H2O2 accumulation in the cells of resistant genotypes is indeed self-destructive, a whole plant phenomenon termed hypersensitive response -cell death at site of infection. The potato callus system thus can be used to gain new insights into the plant-defense response to P. infestans.