Lowering dietary protein content has been proposed to reduce post-weaning diarrhea and enhance gut health of weaned pigs. A series of experiments was conducted to evaluate the effects of low crude protein (LCP) diets in weaned pigs in relation to different nutritional or environmental factors. First, standardized ileal digestible (SID) lysine requirements of 7- to 15-kg weaned pigs were determined using a new genotype of pigs that our research station obtained. The SID lysine requirements for maximum growth of 7- to 15-kg weanling pigs ranged from 1.27 to 1.43%, giving an average value of 1.32%. In the second experiment, the effects of dietary crude protein (CP) content were evaluated in relation to resistant starch supplementation. Feeding LCP diets reduced feed efficiency, decreased incidence of diarrhea and digesta ammonia N content, and enhanced ileum histomorphology in weaned pigs. Dietary supplementation of resistant starch increased the production of beneficial microbial metabolites in the small and large intestines of weaned pigs fed the LCP diet. The third experiment explored the effects of LCP diets and crystalline amino acid supplementation patterns in association with different environmental conditions. Pigs fed LCP diets showed decreased incidence of diarrhea and enhanced the immune system by increasing the plasma anti-inflammatory cytokine profile. However, decreased growth performance was observed in pigs fed LCP diets. Poor sanitation resulted in reduced growth performance in the second week of the trial, however, pigs compensated for the lost growth in the subsequent week. Crystalline amino acid supplementation patterns did not influence growth performance, jejunum histomorphology, or immune response in weaned pigs under different sanitary conditions. However, dietary CP, sanitary conditions, and crystalline amino acid supplementation patterns did not influence colonic bacterial composition and diversity. Overall, lowering dietary protein improved intestinal health of weaned piglets by reducing protein fermentation by the microorganism. Although the growth performance of weaned piglets differed between low- and high-protein diets, feeding LCP diets to weaned pigs can be a nutritional strategy by ameliorating post-weaning diarrhea, improving intestinal morphology, and modulating the microbial profile and metabolites in the gut.