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Simple Summary: Pre-weaned calves have immature immune systems, lack immunocompetence, and often suffer from stress and disease. Diarrhea is a common disease in nursing calves. Antibacterials are widely used in calf production as a common treatment for diarrhea. However, the extensive use of antibacterials can lead to the development of drug-resistant pathogens and endanger public health and safety. Capsaicin is a natural plant extract with antibacterial, anti-inflammatory and antioxidant bioactivities. In this study, we investigated the effects of capsaicin on growth performance, fecal scores, fecal fermentation parameters, antioxidant and immune capacity and the gut microbiota of nursing calves. The results showed that the addition of capsaicin had no effect on calf growth performance and fecal fermentation parameters, improved the antioxidant and immune abilities of calves and also improved the gut microbial environment, which was beneficial for the healthy growth of calves. Capsaicin is the active ingredient of the red pepper plant of the genus Capsicum. The aim of this study was to investigate the effects of different doses of capsaicin on growth performance, antioxidant capacity, immunity, fecal fermentation parameters and gut microbial composition in nursing calves. Twenty-four newborn Holstein calves were randomly assigned to three treatment groups, which each consisted of eight calves. The milk replacer was supplemented with 0, 0.15 or 0.3 mL/d of capsaicin in each of the three treatment groups. During the 4-week experiment, intake was recorded daily, body weight and body size parameters were measured at the beginning and end of the trial and serum samples and rectal fecal samples were collected at the end of the trial to determine serum parameters, fecal fermentation parameters and fecal microbiome compartments. The results showed that both doses of capsaicin had no negative effect on the growth performance or the fecal fermentation parameters of calves, and the higher dose (0.3 mL/d) of capsaicin significantly improved the antioxidant capacity and immunity of calves. The calves in the high-dose capsaicin-treated group had lower fecal scores than those recorded in the control group. High doses of capsaicin increased glutathione antioxidant enzyme, superoxide dismutase, immunoglobulin A, immunoglobulin G, immunoglobulin M and interleukin-10 levels and decreased malondialdehyde and bound bead protein levels. In addition, capsaicin regulated the gut microbiota, reducing the abundance of diarrhea-associated bacteria, such as Eggerthella, Streptococcus, Enterococcus and Enterobacteriaceae, in the gut of calves in the treated group. Therefore, high doses of capsaicin can improve the antioxidant and immune capacity of calves without affecting growth performance, as well as improve the gut microbiological environment, which enables the healthy growth of calves. [ABSTRACT FROM AUTHOR]