Infectious diseases remain a major threat to enhanced poultry production, resulting in significant financial losses and disruptions to productivity and food security. This study tested the efficacy of breeding for improving resistance to infectious bird diseases and compared the immune responses and survival of immigrants. The birds used in this study included an indigenous breed (Local Desi), an improved dual-purpose breed (Rhode Island Red), a commercial layer breed (White Leghorn), a commercial broiler strain, and a CRISPR-mediated MHC-enhanced line. The birds in the controlled challenge were 300, while the replication was 20 per breed × disease combination. The two-way analysis of variance indicated significant effects of breed, disease challenge, and the breed-by-disease interaction on mortality, survival, and antibody titer. The enhanced CRISPR line revealed the lowest average mortality of ≈12–15% while the highest antibody titers were ≈7.5–8.2 log₂ units. The broiler type’s average percentage was the highest at ≈32–38%. The indigenous birds were average as well; they had a stronger immune response than the commercial birds. Pearson’s correlation analysis showed a significant negative association between titer and mortality. r = −0.72, P < 0.001, and a positive association between titer and survival. With r = 0.76 and P < 0.001, a high heterophil-to-lymphocyte ratio correlated positively with mortality, indicating stress-related vulnerability. These results demonstrated substantial genetic variability in resistance characteristics and supported the implementation of genomic and gene-editing methods to promote immune efficiency inquisitiveness in breeding. Also, it helps to increase sustainability.