In Crohn's disease and ulcerative colitis, sulfasalazine reduces the inflammation in the gut that causes flare-ups of these diseases. It is therefore used to control flare-ups, and is also used as a maintenance treatment for ulcerative colitis to prevent further flare-ups.

In rheumatoid arthritis, sulfasalazine reduces inflammation and damage in the joints, and therefore reduces joint swelling and stiffness. It can take up to six weeks for the full effect to be seen in rheumatoid arthritis. In this disease sulfasalazine is known as a disease-modifying antirheumatic drug (DMARD). It is usually only used when non-steroidal anti-inflammatory drugs (NSAIDs) are not working.