Banana Xanthomonas wilt disease caused by Xanthomonas campestris pv. musacearum (Xcm) is a major constraint to production in East and Central Africa. Limitations in classical breeding have prompted the exploration of precise molecular genetic tools like genetic modification and genome editing. All cultivated banana varieties are susceptible to Xcm; the only resistant variety is the progenitor species Musa balbisiana. In our previous study, there was a 5-fold up-regulation of Musa Vicilin gene in the BXW-resistant progenitor species Musa balbisiana, compared to BXW-susceptible banana genotype Pisang Awak, when challenged with Xcm, suggesting involvement of the gene in plant defense. To exploit the defense role of the Musa Vicilin against Xcm, the gene was overexpressed in a susceptible variety Sukali Ndiizi either through a constitutive promoter or by activating the endogenous version using CRISPR activation (CRISPa) at the promote region. Disease resistance and gene expression analyses demonstrated significant differences between transgenic events generated by the two transformation strategies. The transgenic banana events constitutively overexpressing Musa Vicilin gene exhibited enhanced resistance to BXW disease compared to CRISPa MusaVicilin and non-transgenic control plants Therefore, banana transgenic events overexpressing MusaVicilin antimicrobial protein gene have potential to provide resistance against Xanthomonas bacterium. The research was able to generate transgenic bananas that are undergoing further testing with the ultimate goal of providing enhanced BXW resistance under confined field trials.