Fusarium basal rot (FBR) is a serious disease of onion that causes significant losses globally. There are several control measures, of which planting of resistant FBR-cultivars is the most advantageous control option. Thus, to elucidate the involving mechanisms to FBR infection, we consequently carried out quantification changes in antioxidant enzymes activity including ROS (reactive oxygen species); superoxide dismutase (SOD), peroxidase (POX), and catalase (CAT) in two resistant onion genotypes ‘Saba’ and ‘Saba – HS’; and susceptible ‘Savannah Sweet’ and ‘Golden eye’ following inoculation with FBR agent. As a complimentary to the related antioxidant enzymes, we also characterized the critical transcription factors (TFs); R1, R5 and RGA29 marker genes using qRT-PCR involved in endowing resistance at three time course/week post inoculation (wpi). Additionally, we analyzed the changes in biomass growth parameters (BGPs) accordingly. The results showed that the lowest disease severity percentage (DSP) was in resistant ‘Saba’ and ‘Saba – HS’ (6.7 and 4.7 %), and the highest ones in susceptible ‘Savannah Sweet’ and ‘Golden eye’ (88.9 and 89.6%), respectively. There was also a significant increase in CAT, POX, and SOD activities in resistant genotypes. The highest CAT activity was recorded in resistant ‘Saba’- 4.91, and Saba-HS - 3.75 fold, followed by the same trend relatively for POX (‘Saba’- 3.53 and ‘Saba-HS’- 2.35 fold); and SOD (‘Saba’ 14.46 -fold and ‘Saba-HS’ 12.95 –fold) significantly. It was also found that FOC could up-regulate the defense marker genes; R1, PR5, and RGA29 expression in resistant '‘Saba’' and ‘Saba’-HS ranging from 1.23 to 5.01-fold. The highest regulation was in PR5-5.01 fold followed by R1-4.78; and RGA29-3.83-fold, respectively. In addition, BGPs displayed almost similar trends as was in enzyme and gene expression accordingly. These findings lead to introduction of newly FBR-resistant onion genotypes, and also can be implicated in integrated pest management planning programs against FBR disease. Cumulatively, the proteomic-transcriptomic-data provide novel-insights for improving onion-breeding programs against FBR disease.