This study aimed to investigate the effect of yeast cell walls (YCW) on the growth performance, visceral lesions, intestinal integrity, enterotoxicity, and bacteria of broilers challenged with aflatoxin B1 (AF) and necrotic enteritis (NE) from 1 to 21 d of age. A total of 576 one-day-old broilers were assigned to a 2 × 2 × 2 design for diets containing AFB1 (0 or 40 μg/kg), NE (challenged or unchallenged), or YCW (0 or 500 mg/kg). The main effect analysis showed that AF depressed (P < 0.01) average daily feed intake (ADFI), average daily body weight gain (ADG), the mRNA profiles of polymeric Ig receptor (pIgR), claudin-1, and occludin, but increased (P < 0.001) liver lesion scores, serum endotoxin, and diamine oxidase (DAO). The NE challenge depressed (P < 0.01) ADFI, ADG, secretory IgA (sIgA), pIgR, claudin-1, occludin, and the populations of Lactobacilli and Bifidobacteria, but increased (P < 0.001) visceral lesions, endotoxins, and DAO. The main effect of YCW on growth performance, visceral lesions, and intestinal integrity was not significant, but decreased (P < 0.01) mortality, endotoxin, DAO, and C. perfringens, and increased (P < 0.05) the populations of Lactobacilli and Bifidobacteria. There were 3-way interactions (P < 0.05) on growth performance, intestinal lesions, integrity, and gut bacteria. Compared with the treatment with the dual challenges, there were pronounced effects (P < 0.05) of YCW on ADFI, ADG, lesions, DAO, pIgR, and Bifidobacteria. The results suggest that with the concurrent challenges of AF and NE, the YCW can partially protect the growth performance and intestinal health of broilers.