Banana is a major fruit crop in the Philippines and remains to be a large contributor to the country & prime dollar reserve. Among the main hindrances in global banana production, diseases such as Banana bunchy top disease (BBTD) caused by BBTV can bring catastrophic loss to any banana plantation. To elucidate the resistance mechanism and understand the interplay of host factors in the presence of the invading pathogen, we implemented RNA-seq-based comparative transcriptomics analyses of mock- and BBTV-inoculated resistant (wild M. balbisiana) and susceptible (M. acuminata & Lakatan & banana genotypes. Similar patterns of expression for 119 differentially expressed genes (DEGs) were observed on both genotypes, representing the typical defense response of banana to BBTV. A set of 173 DEGs specific to the susceptible ′Lakatan′ banana cultivar revealed potential host factors and susceptibility mechanisms involved in successful BBTV infection. Further, differential transcriptomic analysis revealed 268 DEGs exclusive to the resistant wild M. balbisiana, unraveling insights into the complex resistance mechanisms involved in BBTV defense such as pathogen perception, phytohormone action, reactive oxygen species (ROS), hypersensitive response (HR), production of secondary metabolites, and cell wall modification. The DEGs identified in this study will aid in the design of foreground markers for the precise integration of resistance genes during marker-assisted breeding programs. Furthermore, the application of these results will also enable the foreseen deployment of genome-edited banana cultivars targeting the resistance and host factor genes towards a future-proof banana industry.