Post-weaning diarrhea (PWD) is a major economic loss in the swine industry, caused by factors such as changes in diet, weaning stress, and pathogenic bacteria and viruses. Traditional treatments like antibiotics and zinc oxide have been challenged by resistance and environmental concerns, prompting the search for alternative strategies. This review explores the mechanisms of fluid and electrolyte absorption and secretion in piglets, and the nutritional strategies to control PWD from the perspective of feeds. PWD in piglets is primarily due to an imbalance in intestinal fluid and electrolyte absorption and secretion, often caused by enterotoxigenic Escherichia coli (ETEC) and viral infections. Factors contributing to this imbalance include high crude protein (CP) levels, antigenic proteins, high acid-binding capacity (ABC), and deoxynivalenol (DON) in the diet. Strategies to reduce PWD include lowering CP levels, selecting feedstuffs with lower ABC, and processing feeds using physical, chemical, and biological methods. Supplementation with vitamins and natural products can also help reduce PWD. Mechanisms of fluid secretion and absorption in the intestine involve paracellular and transcellular pathways, with aquaporins (AQPs) playing a key role. Fluid absorption is driven by active transport of Na+ and Cl−, while secretion is driven by Cl− channels and ion transporters. Bacterial and viral infections, such as ETEC and porcine epidemic diarrhea virus (PEDV), can disrupt these mechanisms, leading to diarrhea. Risk factors in feeds include high CP levels, which increase hindgut fermentation and produce toxic metabolites, leading to diarrhea. High ABC values can increase gastric pH, promoting pathogen growth. Antigenic proteins like soybean glycinin and β-conglycinin can cause immune responses and intestinal damage. DON, a common mycotoxin, can damage intestinal cells and induce inflammation, leading to diarrhea. Strategies to reduce PWD include reducing CP levels, using feedstuffs with lower ABC, and processing feeds to inactivate antigens and pathogens. Acidifiers and organic acids can reduce ABC and inhibit pathogenic bacteria. Feed processing methods like biofermentation and enzyme treatment can improve digestion and reduce antigenic proteins. Biological approaches to detoxify DON, such as biodegradation, offer environmentally friendly and efficient solutions. In conclusion, reducing CP levels, managing ABC, and using feed processing techniques are key strategies to control PWD in piglets. These approaches help maintain intestinal health, reduce pathogen infections, and improve growth performance.Post-weaning diarrhea (PWD) is a major economic loss in the swine industry, caused by factors such as changes in diet, weaning stress, and pathogenic bacteria and viruses. Traditional treatments like antibiotics and zinc oxide have been challenged by resistance and environmental concerns, prompting the search for alternative strategies. This review explores the mechanisms of fluid and electrolyte absorption and secretion in piglets, and the nutritional strategies to control PWD from the perspective of feeds. PWD in piglets is primarily due to an imbalance in intestinal fluid and electrolyte absorption and secretion, often caused by enterotoxigenic Escherichia coli (ETEC) and viral infections. Factors contributing to this imbalance include high crude protein (CP) levels, antigenic proteins, high acid-binding capacity (ABC), and deoxynivalenol (DON) in the diet. Strategies to reduce PWD include lowering CP levels, selecting feedstuffs with lower ABC, and processing feeds using physical, chemical, and biological methods. Supplementation with vitamins and natural products can also help reduce PWD. Mechanisms of fluid secretion and absorption in the intestine involve paracellular and transcellular pathways, with aquaporins (AQPs) playing a key role. Fluid absorption is driven by active transport of Na+ and Cl−, while secretion is driven by Cl− channels and ion transporters. Bacterial and viral infections, such as ETEC and porcine epidemic diarrhea virus (PEDV), can disrupt these mechanisms, leading to diarrhea. Risk factors in feeds include high CP levels, which increase hindgut fermentation and produce toxic metabolites, leading to diarrhea. High ABC values can increase gastric pH, promoting pathogen growth. Antigenic proteins like soybean glycinin and β-conglycinin can cause immune responses and intestinal damage. DON, a common mycotoxin, can damage intestinal cells and induce inflammation, leading to diarrhea. Strategies to reduce PWD include reducing CP levels, using feedstuffs with lower ABC, and processing feeds to inactivate antigens and pathogens. Acidifiers and organic acids can reduce ABC and inhibit pathogenic bacteria. Feed processing methods like biofermentation and enzyme treatment can improve digestion and reduce antigenic proteins. Biological approaches to detoxify DON, such as biodegradation, offer environmentally friendly and efficient solutions. In conclusion, reducing CP levels, managing ABC, and using feed processing techniques are key strategies to control PWD in piglets. These approaches help maintain intestinal health, reduce pathogen infections, and improve growth performance.