By the mid-24th century, sufficient advancements in the field led Starfleet to commission the holo-engineer, Dr. Lewis Zimmerman, to begin work at the Jupiter Station Holoprogramming Center on the new EMH program. The design work began around the 2360s, where it took the greatest holo-engineers in Starfleet years to develop the EMH. Among those eventually involved included Reginald Barclay. Following its creation, thousands of holograms based on that technology were created for various functions.

The EMH was designed as "an incredibly sophisticated computer simulation," and "the embodiment of modern medicine." The EMH program specifications, which were at the time considered quite "impressive", included the entire Starfleet Medical Database. In all, it contained over five million medical protocols – ranging from possible treatments to surgical procedures (including one developed by Dr. Leonard McCoy), the collective medical knowledge of over three thousand cultures (including every Federation world), it further possessed information from two thousand medical reference sources (including Gray's Anatomy and Comparative Alien Physiology), and the experience of 47 individual medical officers. Above all, the EMH was programmed with the Hippocratic Oath, that was, an EMH was required that it "do no harm." The universal translator algorithm was written into the EMH's matrix.

It was designed and programmed solely as a short-term emergency supplement to the medical team otherwise found aboard a starship, until a permanent replacement could be found, and therefore, was only meant to function for a maximum of 1,500 hours (62.5 days); after this time, memory degradation would occur.

The EMH was also supplemented with contingency programs and adaptive programs to learn while serving as a supplement of a normal medical staff in cases of emergency. It contained fifty million gigaquads of computer memory, which was "considerably more than most highly developed humanoid brains." Memory files were stored in the EMH memory core, where memories concerning a specific subject or period of time could be deleted. Additionally, while not designed to act as ship's counselor, the EMH had been programmed with sufficient psychological knowledge to note observational concerns.

Beginning around 2370, the entirely new EMH system began to see installation aboard newly launched Intrepid-class and Nova-class starships. By 2371, Starfleet was still being considered for installation throughout the rest of the fleet. In all, 678 Mark Is were created.

Although later deemed to be a design flaw, the EMH had a rather acerbic personality, due primarily to the fact that it was "designed to practice medicine as efficiently as possible," enhancements, such as carrying on small talk or knowledge of "pithy Earth trivia" was viewed by its programmers as means of cluttering up its memory and compromising its performance. Some biological Starfleet doctors even went so far as to object to the use of the EMH. Eventually, it was concluded that the EMH Mark I was defective and they were retired from the Medical Corps. One key factor being that Dr. Zimmerman did not take into account that his own personality, given as that of the EMH, resulted in a poor bedside manner for a medical doctor. The resulting hologram was arrogant and irritable, and as a result was poorly received by many Starfleet doctors. This, in turn, spawned nicknames like "Emergency Medical Hotheads" and "Extremely Marginal Housecalls." According to Zimmerman he tried to save face and have them decommissioned, but "Starfleet, in its infinite wisdom, overruled me and reassigned them all to work waste transfer barges." Later, the Mark Is were also deployed in other menial tasks, like dilithium mining.

To address the flaws in the EMH Mark I, Dr. Zimmerman began work on the Mark II, a prototype of which was finished in time to be included in the sickbay of the USS Prometheus in 2374. While the Mark I's outward appearance was a copy of its inventor, a disillusioned Dr. Zimmerman changed the outward appearance of the Mark II. Furthermore, the patterns of behavior of the following versions were designed to be more pleasant and courteous. To achieve this, Zimmerman initially tried to improve on the programming of the Mark I, but eventually decided to create the Mark II from scratch. In addition to that, new ship designs like the USS Prometheus enabled full mobility for the EMH, as the whole ship was outfitted with holographic projectors.

By 2377, the Mark II had been replaced by a Mark III, followed by a Mark IV. By late century, EMH programs, as well as variations on the "emergency" theme, were all incorporated into the customizable Emergency Hologram basic installation, which was available for civilian use. Such packages were available onboard Kaplan F17 Speed Freighters.

EMH programs continued to be used by the Federation and Starfleet, well into the 32rd century.