Simple Summary Raising dairy calves poses a dual challenge for the dairy industry-economically and physiologically. The industry seeks innovative solutions that can not only reduce dependence on antibiotic treatments but also enhance the overall wellbeing, gastrointestinal tract development, and performance of young calves. Among the potential solutions, butyrate supplementation has emerged as a promising tool. To validate this hypothesis, the present study meticulously assesses the impact of butyrate supplementation on key parameters such as feed intake, gastrointestinal tract development, health, and performance of pre-weaned dairy calves. Furthermore, this investigation delves into the lasting effects of butyrate supplementation post weaning.Abstract Diarrhea and respiratory diseases pose significant challenges in the rearing of pre-weaned calves, motivating the investigation of tools to improve gastrointestinal tract development, health, and overall performance in young calves. Consequently, the primary objective of this study was to assess the effectiveness of an additive incorporated into milk replacer to promote the development and health of the animals. Forty-six dairy calves were randomly assigned into two treatments: control (CON, n = 23; with 15 females and 8 males), and sodium butyrate (SB, n = 23; with 15 females and 8 males). The calves in the SB treatment group were supplemented with 4 g/d of unprotected sodium butyrate (Adimix, Adisseo, China), added to the milk replacer from 4 to 60 days of age. Water and starter were fed ad libitum. The study evaluated several parameters, including feed intake, nutrient digestibility, ruminal pH, ammonia and volatile fatty acids, blood metabolites (glucose, insulin-like growth factor type 1, urea, beta-hydroxybutyrate), hemogram, health scores, performance, and feed efficiency. Bull calves were euthanized at 60 days of age for organ comparison, while heifer calves were assessed for carryover effects up to 90 days of age. Data were analyzed independently using linear mixed models using the nlme package in R, and the Artools package for non-parametric categorical outcomes. Although the feed intake and performance variables exhibited differences within weeks, no divergence was observed between treatment groups. Notably, a positive treatment-by-week interaction was identified for starter feed intake (p = 0.02) and total dry matter intake (p = 0.04) during pre-weaning for CON animals. Ruminal parameters, blood metabolites, and hemogram values such as glucose, urea, insulin-like growth factor type 1, mean corpuscular value, lymphocytes, and neutrophils displayed differences within weeks during the pre-weaning stage, but similar results within groups. No differences between supplemented and non-supplemented calves were found across nutrient digestibility, organ development, and histology. Regarding health scores, differences were noted within weeks for fecal and respiratory scores during the pre-weaning stage, and only the respiratory score during the post-weaning stage. Consequently, butyrate supplementation did not elicit improvements or negative effects in the body development or health status of dairy calves.