Avian coccidiosis is an infectious parasitic disease that triggers severe intestinal inflammation, leading to nutrient malabsorption, bleeding, and even death. Here we evaluated the response of coccidia-challenged birds to dietary multienzyme (phytase, xylanase, β-glucanase, amylase, hemicellulases, and pectinases) supplementation. In a 21-day trial, Ross 308 broiler chickens were allotted to a 2×2 factorial arrangement consisting of 0 or 25 g/kg multienzyme and challenge with PBS or Eimeria oocysts. Coccidia challenge by oral gavage with multiple Eimeria spp. oocysts (50,000 E. maxima, 50,000 E. tenella, and 250,000 E. acervulina) was introduced on day 13 post hatching. The multienzyme alleviated (P < 0.05) Eimeria-induced reduction in feed efficiency and nutrient utilization. Multienzyme supplementation reversed (P < 0.05) the upregulation of pro-inflammatory cytokine IL-8 in duodenum and jejunum resulting from Eimeria spp. infection. The expression of amino acids transporter b0,+AT was upregulated (P < 0.05) in the jejunum following multienzyme treatment. The ileal expression of antioxidant HMOX1 was induced (P = 0.05) in the multienzyme group with coccidia challenge. Coccidiosis decreased (P < 0.05) the diversity and modulated the composition of microbial communities in ileum and ceca. Coccidia challenge facilitated (P < 0.01) the colonization of opportunistic pathogens such as Actinobacillus, Bacillus, and Streptococcus, and inhibited (P < 0.01) the growth of cecal beneficial microbiota such as Bifidobacterium, Clostridia_UCG-014, and Facecalibacterium. Multienzyme supplementation increased (P < 0.01) the proliferation of beneficial bacteria, especially SCFA-producers and fiber-degrading genus, such as Anaerostipes, Butyricicoccus, and Pseudoscardovia.