Acute treatment uses medications to treat any infection (normally antibiotics) and to reduce inflammation (normally aminosalicylate anti-inflammatory drugs and corticosteroids). When symptoms are in remission, treatment enters maintenance, with a goal of avoiding the recurrence of symptoms. Prolonged use of corticosteroids has significant side-effects; as a result, they are, in general, not used for long-term treatment. Alternatives include aminosalicylates alone, though only a minority are able to maintain the treatment, and many require immunosuppressive drugs. It has been also suggested that antibiotics change the enteric flora, and their continuous use may pose the risk of overgrowth with pathogens such as "Clostridium difficile".

Medications used to treat the symptoms of Crohn's disease include 5-aminosalicylic acid (5-ASA) formulations, prednisone, immunomodulators such as azathioprine (given as the prodrug for 6-mercaptopurine), methotrexate, infliximab, adalimumab, certolizumab and natalizumab. Hydrocortisone should be used in severe attacks of Crohn's disease. Biological therapies (biopharmaceuticals) are medications used to avoid long-term steroid use, decrease inflammation, and treat people who have fistulas with abscesses. The monoclonal antibody ustekinumab appears to be a safe treatment option, and may help people with moderate to severe active Crohn's disease. The long term safety and effectiveness of monoclonal antibody treatment is not known. The monoclonal antibody briakinumab is not effective for people with active Crohn's disease.

The gradual loss of blood from the gastrointestinal tract, as well as chronic inflammation, often leads to anemia, and professional guidelines suggest routinely monitoring for this. Adequate disease control usually improves anemia of chronic disease, but iron deficiency may require treatment with iron supplements. Guidelines vary as to how iron should be administered. Besides other, problems include a limitation in possible daily resorption and an increased growth of intestinal bacteria. Some advise parenteral iron as first line as it works faster, has fewer gastrointestinal side effects, and is unaffected by inflammation reducing enteral absorption.

Other guidelines advise oral iron as first line with parenteral iron reserved for those that fail to adequately respond as oral iron is considerably cheaper. All agree that severe anemia (hemoglobin under 10g/dL) should be treated with parenteral iron. Blood transfusion should be reserved for those who are cardiovascularly unstable, due to its relatively poor safety profile, lack of long term efficacy, and cost.

Crohn's may result in anxiety or mood disorders, especially in young people who may have stunted growth or embarrassment from fecal incontinence. Counselling as well as antidepressant or anxiolytic medication may help some people manage.

As of 2017 there is a small amount of research looking at mindfulness-based therapies, hypnotherapy, and cognitive behavioural therapy.

Between 0.3% and 10% of people have refractory disease, which means that they have persistent villous atrophy on a gluten-free diet despite the lack of gluten exposure for more than 12 months. Nevertheless, inadvertent exposure to gluten is the main cause of persistent villous atrophy, and must be ruled out before a diagnosis of refractory disease is made. People with poor basic education and understanding of gluten-free diet often believe that they are strictly following the diet, but are making regular errors. Also, a lack of symptoms is not a reliable indicator of intestinal recuperation.

If alternative causes of villous atrophy have been eliminated, steroids or immunosuppressants (such as azathioprine) may be considered in this scenario.

Refractory coeliac disease should not be confused with the persistence of symptoms despite gluten withdrawal caused by transient conditions derived from the intestinal damage, which generally revert or improve several months after starting a gluten-free diet, such as small intestinal bacterial overgrowth, lactose intolerance, fructose, sucrose, and sorbitol malabsorption, exocrine pancreatic insufficiency, and microscopic colitis, among others.

At present, the only effective treatment is a lifelong gluten-free diet. No medication exists that will prevent damage or prevent the body from attacking the gut when gluten is present. Strict adherence to the diet allows the intestines to heal, leading to resolution of all symptoms in most cases and, depending on how soon the diet is begun, can also eliminate the heightened risk of osteoporosis and intestinal cancer and in some cases sterility. The diet can be cumbersome; failure to comply with the diet may cause relapse.

Dietitian input is generally requested to ensure the person is aware which foods contain gluten, which foods are safe, and how to have a balanced diet despite the limitations. In many countries, gluten-free products are available on prescription and may be reimbursed by health insurance plans. Gluten-free products are usually more expensive and harder to find than common gluten-containing foods. Since ready-made products often contain traces of gluten, some coeliacs may find it necessary to cook from scratch.

The term "gluten-free" is generally used to indicate a supposed harmless level of gluten rather than a complete absence. The exact level at which gluten is harmless is uncertain and controversial. A recent systematic review tentatively concluded that consumption of less than 10 mg of gluten per day is unlikely to cause histological abnormalities, although it noted that few reliable studies had been done. Regulation of the label "gluten-free" varies. In the European Union, the European Commission issued regulations in 2009 limiting the use of "gluten-free" labels for food products to those with less than 20 mg/kg of gluten, and "very low gluten" labels for those with less than 100 mg/kg. In the United States, the FDA issued regulations in 2013 limiting the use of "gluten-free" labels for food products to those with less than 20 ppm of gluten. The current international Codex Alimentarius standard allows for 20 ppm of gluten in so-called "gluten-free" foods. Several organisations, such as the Gluten-Free Certification Organization (GFCO), the Celiac Sprue Association (CSA), and the National Foundation for Celiac Awareness (NFCA), also certify products and companies as gluten-free.

Gluten-free diet improves healthcare-related quality of life, and strict adherence to the diet gives more benefit than incomplete adherence. Nevertheless, gluten-free diet doesn't completely normalise the quality of life.