During the fifth and final year of the U.S.S. Enterprise's historic five-year mission, the starship's senior medical officer and chief surgeon, Dr. Leonard H. McCoy, revealed a dimension of his life he had previously kept to himself: his life as a family man and father. When a Vendorian shape-changer disguised as the long-missing interstellar tycoon and philanthropist Carter Winston came aboard the Enterprise on stardate 5143.3 (2269), McCoy mentioned the existence of a 20-year-old daughter named Joanna who had attended school a decade earlier on the famine-stricken Federation colony known as Cerberus, a planet that had been fortunate enough to be saved from disaster by Winston's humanitarian intervention.

Though he remained in charge of the Enterprise's sickbay, Dr. McCoy saw his share of action in the field throughout 2269. On stardate 5554.8, McCoy helped rescue Commander Spock from the clutches of the misguided genetic engineer Dr. Stavos Keniclius 5 on the planet Phylos by deploying a weed-spray recipe developed by one of McCoy's remote ancestors from the American South; the spray immobilized the fierce airborne Phylosian plant creatures known as "swoopers.? On stardate 5267.6, McCoy found himself in a brief fistfight with a member of Captain Kor's Klingon crew in the extradimensional realm of Elysia, which prompted the extremely violence-averse Elysians to consider placing the Klingon crew of the I.K.S. Klothos into a century-long hibernation — a decision that would have left the crew of the Enterprise stranded just as much as the Klingons, whose help the Enterprise crew needed to escape from Elysian space. McCoy and Lieutenants Sulu and Uhura subsequently almost froze to death in blizzard conditions created inside one of the Enterprise's recently upgraded recreation rooms on stardate 3183.3, after the room's computerized environmental controls had been seized by a disembodied entity bent on performing a series of sometimes deadly "practical jokes.?

On stardate 5275.6, McCoy was arrested by the law-enforcement authorities on Dramia II, where the doctor stood accused of causing a plague on another Dramian world 19 years earlier while he had been administering a mass inoculation program there. When an outbreak of so-called "auroral plague? swept through the Enterprise at the same time, Spock broke McCoy out of jail in time to allow him to find a cure, and to help McCoy prove that the disease outbreak of nearly two earlier had really been caused by a planetary aurora, and had spread by a Dramian named Demos rather than by McCoy.

After the conclusion of the Enterprise's historic five-year mission, Dr. McCoy retired from Starfleet to begin a private medical practice on Earth, in his native state of Georgia. And although he had sworn he would never go back to Starfleet, he returned to active duty on stardate 7412.3 (2271) after Admiral James Kirk invoked a little known, seldom used reserve activation clause in McCoy's Starfleet commission contract. Although McCoy complained bitterly about Kirk's summons at the time, he returned to his old post for the duration of the immediate V'Ger crisis, and remained on active duty in Starfleet for the next 22 years; he stayed on in the service in a reserve capacity for many decades thereafter, briefly coming aboard the U.S.S. Enterprise-D as a visiting admiral on stardate 41153.7 (2364).