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Butyrate is a short-chain fatty acid (SCFA) created within the intestinal lumen by bacterial fermentation of largely undigested dietary carbohydrates. Its beneficial effects on cellular energy metabolism and intestinal homeostasis have garnered significant attention among SCFAs. Butyrate also has systemic effects and is known to regulate the immune system. Most of the butyrate and other SCFAs are produced in the human colon, through the fermentation of dietary fiber or resistant starch. However, the modern diet often lacks sufficient intake of fermentable dietary fiber, which can lead to low butyrate levels in the colon. To increase butyrate levels, it is helpful to incorporate fiber sources into meals and drinks that rely on slow bacterial fermentation. Butyrate is well known for its anti-inflammatory properties and has a range of immune system-related properties. As an agonist for GPR41, GPR43, or GPR109A, butyrate may have anti-inflammatory effects through these receptors’ signaling pathways. Butyrate also serves as an epigenetic regulator, responding to environmental or pharmacological changes by inhibiting HDAC, up-regulating miR-7a-5p, and promoting histone butyrylation and autophagy processes. This review discusses the importance of butyrate in regulating immunological homeostasis and the inflammatory response. It also addresses experimental models and human studies investigating the therapeutic potential of butyrate supplementation in immune-related conditions linked to butyrate depletion. Specifically, it covers the role of butyrate in some immune-related diseases such as systemic lupus erythematosus, atopic dermatitis, psoriasis, human immunodeficiency virus, cancer, and several other special conditions.