Proteomics of wild and cultivated tomato species challenged with Alternaria solani revealed altered protein profile with 1827 proteins in challenged susceptible plants (KTr), 1867 in non-challenged plants (KNTr), 1721 in challenged wild (CTr) and 1715 in non-challenged plants (CNTr). PLS-DA and heatmap analysis highlighted differences in protein composition and abundance as differential response species to pathogen. Compared to 321 differentially expressed proteins (DEPs) in wild tomato, cultivated plants showed 183 DEPs. Key upregulated proteins in wild tomato included defense-related t-SNARE, glucan endo-1,3-beta-D-glucosidase, pathogenesis-related protein P2, stress responsive DEK domain containing protein, heat shock 70 kDa protein 17, SHSP chaperone, signaling linked DAG, SCP domain-containing protein, Cutin-deficient protein, immunity-related translation initiation factor and RRM domain-containing protein. Protein-protein interaction (PPI) network analysis clustered defense related up-regulated chaperonins and other proteins into three distinct clusters in wild tomato. Prominent subcellular locations of up-regulated proteins were extracellular and intracellular regions, cytoplasm and membrane bound organelles. Compared to cultivated species, majority of plant defense, stress response and growth-related protein biomarkers were found up-regulated in wild tomato, suggesting its tolerance against pathogen due to stronger response. We conclude that significant up-regulation of defense, signaling and plant growth-related proteins enabled wild species to mount stronger response against the pathogen A. solani. Higher compositional protein diversity in the wild plants likely provided metabolic plasticity to modulate intrinsic defense mechanisms more effectively. This study enhances our understanding of the proteome-related molecular mechanisms underlying differential responses of wild and cultivated tomato species to this devastating pathogen.