Early blight disease (EB), Alternaria alternata, is destructive on Solanum lycopersicum Mill. The responses of 35 domestic and exotic commercial tomato genotypes to early blight were examined at transplanting and maturing stages using genetic diversity analysis, with 15 Inter Simple Sequence Repeat (ISSR) primers, total phenolic content (TPC), and enzymatic activity of catalase (CAT), phenylalanine ammonia lyase (PAL), peroxidase (POD) and superoxide dismutase (SOD) assays. The disease severity ranged from 18 to 87.5%. Eleven of 15 ISSR primers generated 68 loci of which 63 (90%) were polymorphic. Polymorphism information content value varied from 0.3 to 0.5 with an average of 0.4. Nei's measure of the average gene diversity ranged from 0.06 to 0.5. The Tomato genotypes were divided into five clusters in Un-weighted Pair Group Method with Arithmetic Mean (UPGMA) analysis, showing a considerable similarity between resistance level and molecular classification pattern. Antioxidant analysis indicated a significant increase in TPC and CAT, POD, PAL and SOD activities in most inoculated tomato genotypes at both growth stages. The highest increase in activity was seen in PAL (5-fold) and TPC (4-fold) at transplanting stage, whereas the highest TPC (2 to 3-fold) and POD activity (3-fold) were found at maturing stage in all the inoculated resistant genotypes in comparison with controls. Esfahan Local and H. a.s 2274 showed the highest level of activity in POD (2.5- and 3- fold, respectively) and TPC (2.5- and 4-fold, respectively). Our results suggest that using both genetic diversity and enzymatic diversity as markers, it is possible to discriminate resistant from susceptible tomato genotypes to early blight disease.