For Commander Spock, first officer and science officer of the U.S.S. Enterprise, the final year of the Enterprise's five-year mission of exploration began traumatically. On stardate 5373.4 (2269) — on the arid, long-dead homeworld of the mysterious time portal known as the Guardian of Forever — Spock discovered that most of his life had somehow been erased during a routine historical survey; to put matters right, Spock was forced to use the Guardian to return to his own past on his home planet Vulcan, where he prevented the death of his seven-year-old self on the eve of the child's coming-of-age rites (known collectively as the kahs-wan test) — at the cost, poignantly, of the life of I-Chaya, Spock's beloved pet, a giant teddy-bear-like creature called a sehlat.

On stardate 5372.1 (2269), Spock mind-melded with a planet-devouring, 800,000-kilometer-wide intelligent cloud-entity, persuading it in the proverbial nick of time to spare the remote Federation colony world of Mantilles from destruction, and gaining insight into hitherto unglimpsed wonders of the universe in the process. A short time later (stardate 5554.4) on the newly-discovered planet Phylos, Spock was captured by members of that world's plant-based sentient species and turned over to Dr. Stavos Keniclius 5, the clone of a genetic scientist who had participated in Earth's Eugenics Wars in the late twentieth century. Keniclius 5 created a giant clone of Spock as part of a plan to create a huge cadre of genetically engineered beings with which Keniclius would forcibly impose his own idea of "peace? upon the entire galaxy. This plan, which would have resulted in the death of the original Spock, fell apart because of the inherent logic and decency of the Spock clone, who — like the original Spock — could not be made to behave unethically or illogically. Shortly thereafter, Spock briefly fell in love with Nurse Christine Chapel after being exposed to Harry Mudd's "love crystals? on stardate 4978.5. Then, along with Captain Kirk, Spock briefly became a water-breather on the pelagic planet Argo on stardate 5499.9. A short time later (stardate 4187.3), Spock commanded the Shuttlecraft Copernicus, accompanied by Lieutenants Sulu and Uhura, during an encounter with a group of Kzinti who sought to steal a Slaver stasis box that Spock and his team were attempting to transport to Starbase 25. Although the Kzinti, led by Chuft Captain, had hoped to gain control of the powerful ancient Slaver weapon that had been stored inside the stasis box for upwards of a billion years, their plans came to nothing through a combination of the machinations of Spock and his crewmates, as well as actions taken by the weapon's own internal machine intelligence.

On stardate 6334.1 (2269), Spock contracted choriocytosis, a disease that in most species with iron-based blood causes symptoms no more serious than pneumonia; unfortunately, choriocytosis is uniformly lethal to copper-blooded species, such as Vulcans. Spock survived and recovered because Captain Kirk pursued and captured an Orion pirate captain who had stolen a Starfleet cargo that included the drug strobolin, the only substance capable of curing the disease. When an outbreak of so-called "auroral plague? swept through the Enterprise on stardate 5275.6, Spock was the only member of the crew immune to the disease; Spock was therefore able to break Dr. McCoy out of the Dramian jail where he was being held on suspicion of having started another plague outbreak some 19 years earlier, thus enabling McCoy to find a cure for the new affliction in time to save the lives of Captain Kirk and the rest of the Enterprise's crew complement. Spock's actions also helped McCoy demonstrate that the disease of nearly two decades earlier had actually been caused by a planetary aurora, and had been spread by a Dramian named Demos rather than by McCoy. On stardate 6770.3, Spock regressed in age back to childhood, along with the rest of the Enterprise crew, as a consequence of the ship's accidental passage into a time-reversed antimatter universe. Fortunately he retained enough of his Starfleet training to assist Commodore Robert April — temporarily in command of the Enterprise — in getting the ship back into normal space. Afterward, a trip through the transporter, which retained every crewmember's original molecular pattern data, restored all the "children? aboard to their normal ages.

After the conclusion of 2269 — and the close of the Enterprise's pioneering five-year exploration mission — Spock retired from Starfleet, returning to Vulcan to purge all of his remaining human emotion by means of the rigorous Kolinahr training. This severely ascetic regimen was nearly complete by stardate 7410.2 (2271), when Spock's telepathic and emotional sensitivities responded to the approach of the V'Ger entity, prompting an emotional response in Spock in the presence of his Vulcan Masters (teachers) that prevented his attainment of Kolinahr. Spock's subsequent search for answers to the riddle posed by his momentary but intense contact with V'Ger drew the former Starfleet science officer back to his old captain and crewmates, and put him on a course toward the captaincy of the Enterprise, to which Starfleet would appoint him by stardate 8130.3 (2285).