Newcastle disease (ND) is a highly contagious viral disease that constantly threatens poultry production. The velogenic (highly virulent) form of ND inflicts the most damage and can lead to 100% mortality in unvaccinated village chicken flocks. This study sought to characterize responses of local chickens in Ghana after challenging them with lentogenic and velogenic Newcastle disease virus (NDV) strains. At 4 wk of age, chicks were challenged with lentogenic NDV. Traits measured were pre- and post-lentogenic infection growth rates (GR), viral load at 2 and 6 d post-lentogenic infection (DPI), viral clearance rate and antibody levels at 10 DPI. Subsequently, the chickens were naturally exposed to velogenic NDV (vNDV) after anti-NDV antibody titers had waned to levels ≤1:1,700. Body weights and blood samples were again collected for analysis. Finally, chickens were euthanized and lesion scores (LS) across tissues were recorded. Post-velogenic exposure GR; antibody levels at 21 and 34 days post-velogenic exposure (DPE); LS for trachea, proventriculus, intestines, and cecal tonsils; and average LS across tissues were measured. Variance components and heritabilities were estimated for all traits using univariate animal models. Mean pre- and post-lentogenic NDV infection GRs were 6.26 g/day and 7.93 g/day, respectively, but mean post-velogenic NDV exposure GR was -1.96 g/day. Mean lesion scores ranged from 0.52 (trachea) to 1.33 (intestine), with males having significantly higher (P < 0.05) lesion scores compared to females. Heritability estimates for the lentogenic NDV trial traits ranged from moderate (0.23) to high (0.55) whereas those for the vNDV natural exposure trial were very low (≤ 0.08). Therefore, in contrast to the vNDV exposure trial, differences in the traits measured in the lentogenic challenge were more affected by genetics and thus selection for these traits may be more feasible compared to those following vNDV exposure. Our results can form the basis for identifying local chickens with improved resilience in the face of NDV infection for selective breeding to improve productivity.