In this comparative study, the differential responses of heritage (ACRB; Athens Canadian Random Bred) and modern (Cobb) broilers to a necrotic enteritis (NE) challenge were evaluated. The design was a 2×2 factorial with breed (ACRB and Cobb) and challenge (non-challenged and NE-challenged) as main factors. On day (d) of hatch, 96 male chicks (48 ACRB and 48 Cobb) were allocated to 4 experimental groups with 8 replicate cages and 3 birds/cage. On d 14, birds in the NE-challenged groups were orally gavaged with 3,000 Eimeria maxima sporulated oocysts followed by 2 doses of ∼1×108 CFU of Clostridium perfringens on d 19 and 20. On d 21, 2 birds/cage were necropsied to score NE lesions, and spleen and cecal tonsils (CT) samples were collected from 1 bird/cage for assessing mRNA abundance. Challenged ACRB birds exhibited reduced growth performance and relative growth performance compared to challenged Cobb birds. There was no significant interaction between breed and challenge during the challenge period (d 14-21) for mortality. However, there was a challenge main effect (P ≤ 0.05) on mortality as manifested by greater NE-associated mortality compared to non-challenged birds. No significant breed × challenge interaction or breed main effect on lesion scores were observed in the duodenum, jejunum, and ileum. NE-challenged Cobb birds exhibited greater mRNA abundance of IL-18, TNFα, TLR1.2, TLR2.1, CCR5, CCR6, CCL20, and AvBD1 in CT compared to NE challenged ACRB birds. There was a significant breed × challenge interaction effect on mRNA abundance of IL-10, AvBD13, NK-Lysin, and LEAP2 in the spleen. Moreover, a main effect of breed was observed in IL-1β, IL-18, TNFα, TLR2.1, CCR5, CCL20, and NK-Lysin where ACRB birds had higher mRNA abundance than Cobb birds (P ≤ 0.05). The observed differences in performance, pathology, and mRNA abundance between ACRB and Cobb broilers during the NE challenge highlight the distinct immune response profiles of heritage and modern breeds, emphasizing the need for breed-specific nutritional, managerial, and genetic selection programs for modulating immune responses during enteric disease challenges.