The GI tract, from beginning to end, is made up of four continuous tissue layers that adjust their structure according to their specific roles. These layers, from innermost to outermost, are known as the mucosa, submucosa, muscularis, and serosa, which are continuous with the mesentery.

The mucosa is sometimes called a mucous membrane due to its mucus-secreting features. This membrane is composed of epithelium, which directly interacts with ingested substances, and the lamina propria, a layer of connective tissue. A slim layer of smooth muscle, called the muscularis mucosae, is also part of the mucosa.

The epithelium varies in its structure. It is primarily a non-keratinized, stratified squamous epithelium in the mouth, pharynx, esophagus, and anal canal. However, it's a simple columnar epithelium in the stomach and intestines. The epithelium also houses goblet cells that release mucus and enteroendocrine cells which secrete hormones. The epithelium cells have a short lifespan, allowing for frequent renewal, which helps maintain the health of the GI tract by replacing damaged or worn-out cells regularly.

The lamina propria comprises loose connective tissue and numerous blood and lymphatic vessels that help distribute absorbed nutrients. In addition, it houses lymphocytes, forming the mucosa-associated lymphoid tissue (MALT) for immune responses.

The muscularis mucosae is a layer of smooth muscle that aids in the movement of secretions through peristalsis.

Beneath the mucosa lies the submucosa, made up of dense connective tissue. It connects the mucosa to the muscularis and includes blood and lymphatic vessels, glands for digestive secretions, and a network of nerves known as the submucosal plexus.The submucosa layer primarily forms the larger folds that increase surface area, like rugae in the stomach and plicae circulares in the small intestine.

The muscularis (also referred to as the muscularis externa) is the third layer of the GI tract. It promotes mechanical digestion and the movement of food along the canal through contractions. The muscularis varies as per the region of the GI tract.

The serosa is the outermost layer of the GI tract, present only in the abdominal cavity. It comprises a layer of visceral peritoneum on top of a layer of loose connective tissue. In the mouth, pharynx, and esophagus, a dense collagen fiber sheath called the adventitia replaces the serosa, helping anchor the GI tract near the vertebral column's ventral surface.