This study was conducted to investigate the impact of dietary inclusion of
Moringa oleifera
leaf meal (MLM) as a substitution for soybean meal on nutrient digestibility, rumen fermentation, rumen enzyme activity, blood metabolites, growth-related hormones, and growth performance of buffalo calves. Thirty buffalo calves eight to nine months of age with an average body weight of approximately 153.7 ± 0.97 kg were randomly distributed through three dietary treatments (ten calves/treatment). MLM inclusion rates were 15% (M15) and 20% (M20), replacing soybean meal by 50 and 75% in the concentrate mixture, respectively. The results indicated that, digestibility of dry matter, organic matter (OM), and crude fiber (CF) increased significantly (p < 0.05) with MLM inclusion, while the digestibility of crude protein (CP) and ether extract (EE) reduced significantly (p < 0.05) with MLM addition. Dietary supplementation with MLM significantly affected (p < 0.001) rumen fermentation by reducing ruminal enzymes, ruminal ammonia-N, total protozoa, and acetate/propionate ratio and increasing acetic, propionic, and butyric acids and total volatile fatty acid concentrations (p < 0.001). Furthermore, dietary inclusion of 15% MLM significantly improved (p < 0.001) final body weight, dry matter intake of feed, daily weight gain, feed conversion efficiency, blood metabolites, and plasma insulin growth factor-I (IGF-I). It can be concluded that MLM is a multi-purpose protein supplement that provides some nutritional and therapeutic advantages when replacing 50% of soybean meal. Dietary supplementation of 15% MLM improved rumen fermentation, growth performance, blood metabolites, plasma IGF-I and mitigated ammonia and methane without any adverse effects in growing buffalo calves.