The patient is kept NPO (Nil per os) or NBM (Nothing By Mouth) that is, told not to eat, for at least 4–6 hours before the procedure. Most patients tolerate the procedure with only topical anesthesia of the oropharynx using lidocaine spray. However, some patients may need sedation and the very anxious/agitated patient may even need a general anesthetic. Informed consent is obtained before the procedure. The main risks are bleeding and perforation. The risk is increased when a biopsy or other intervention is performed.

The patient lies on his/her left side with the head resting comfortably on a pillow. A mouth-guard is placed between the teeth to prevent the patient from biting on the endoscope. The endoscope is then passed over the tongue and into the oropharynx. This is the most uncomfortable stage for the patient. Quick and gentle manipulation under vision guides the endoscope into the esophagus. The endoscope is gradually advanced down the esophagus making note of any pathology. Excessive insufflation of the stomach is avoided at this stage. The endoscope is quickly passed through the stomach and through the pylorus to examine the first and second parts of the duodenum. Once this has been completed, the endoscope is withdrawn into the stomach and a more thorough examination is performed including a J-maneuver. This involves retroflexing the tip of the scope so it resembles a 'J' shape in order to examine the fundus and gastroesophageal junction. Any additional procedures are performed at this stage. The air in the stomach is aspirated before removing the endoscope. Still photographs can be made during the procedure and later shown to the patient to help explain any findings.

In its most basic use, the endoscope is used to inspect the internal anatomy of the digestive tract. Often inspection alone is sufficient, but biopsy is a very valuable adjunct to endoscopy. Small biopsies can be made with a pincer (biopsy forceps) which is passed through the scope and allows sampling of 1 to 3 mm pieces of tissue under direct vision. The intestinal mucosa heals quickly from such biopsies.

Biopsy allows the pathologist to render an opinion on later histologic examination of the biopsy tissue with light microscopy and/or immunohistochemistry. Biopsied material can also be tested on urease to identify Helicobacter pylori.

Upper GI endoscopy is the most accurate way to provide screening for Barrett’s esophagus, a complication of long-standing reflux esophagitis (GERD) which can lead to esophageal cancer if not detected in time.