Since Alagille syndrome affects several organ systems at once, care is best coordinated by a team that typically includes a clinical geneticist along with specialists in liver disease, heart disease, nutrition, kidney disease, and eye disease, with an organ transplant specialist involved when needed.

Liver-related symptoms, particularly intense itching and impaired bile flow, are usually the most limiting day-to-day problem, and management here has changed meaningfully in recent years:
• Ileal bile acid transporter inhibitors — maralixibat (approved for children older than three months) and odevixibat (approved for children older than twelve months) — have received approval from the United States regulatory health authority specifically for the impaired bile flow of Alagille syndrome. Both work by increasing the amount of bile acid removed through the stool rather than reabsorbed into the body, which can meaningfully reduce itching and is associated with improved event-free survival with the person’s own liver.
• Other medications for itching and fatty skin deposits include ursodeoxycholic acid, cholestyramine, rifampin, and naltrexone.
• Biliary diversion, a surgical procedure to divert bile away from the intestine, is sometimes used when medications are not enough.
• Liver transplantation may be needed when liver disease cannot be adequately controlled. Roughly half of individuals with a history of newborn impaired bile flow eventually require a transplant by adulthood, most commonly within the first five years of life, and survival after transplant is favourable, at about eighty-eight percent by twenty years of age.

Other aspects of care include:
• Correcting deficiencies of the fat-soluble vitamins A, D, E, and K, which are poorly absorbed when bile flow is reduced.
• Optimizing calorie intake, sometimes with a feeding tube, to support growth
• Treatment of congenital heart defects by a cardiologist, which may include a catheter-based procedure or surgery depending on severity.
• Monitoring and management of kidney, skeletal, and developmental concerns as they arise.
• Avoiding contact sports for individuals with significant liver or spleen enlargement, because of injury risk, and avoiding alcohol for anyone with liver disease.

Each individual with Alagille syndrome presents the condition differently, symptoms observed in one may not manifest in others. Each individual with Alagille syndrome is advised to get a detailed evaluation to schedule a treatment plan tailored to them.