Keyes was born on Earth and spent some time around the Pacific Ocean during his childhood. It is likely that he attended an Officer Candidate School, During his second year of training an incident occurred where fourteen ensigns were killed due to an instructor's error during a poorly planned test. Keyes suffered plasma burns during the test and had to be rehabilitated in a hospital for two months. Keyes refused to testify against the instructor and was nearly demoted for it. Keyes' stubbornness is what brought him to the attention of Dr. Halsey.

In 2517, seven weeks out of the OCS, Lieutenant (J.G.) Keyes was assigned to the UNSC Magellan when those orders were rescinded and he was chosen to assist Dr. Catherine Halsey with her task of searching for usable subjects for her SPARTAN-II project. In order to fool anybody who were suspicious, they told them that they were looking for a school for their daughter, and the both of them began observing the chosen subjects for the program. The first child they chose was SPARTAN subject number 117: John. Keyes never forgot this assignment or the names of each and every one of those children.

As Keyes slowly started learning of the true nature of the SPARTAN-II project, Dr. Halsey immediately sent him back to normal duty with a full Lieutenant commission and he became an excellent strategist, especially when dealing with Covenant. Early in the Human-Covenant War, he became a foremost hero when he led a small group of security troops against a Covenant ambush of the frigate UNSC Meriwether Lewis and held the Covenant off long enough for the ship to escape. He sustained a deep gauging plasma burn to his thigh and had his hand shattered, which was later rebuilt. He later toured on the Frigate UNSC Midsummer Night. He garnered many citations and years of combat experience against the Covenant during these tours. During one of these tours, Keyes went to Charybdis IX. There, he killed his first human being with a modified Plasma Rifle, during a riot.

Shortly after this confrontation, Charybdis IX was glassed by the Covenant. The Midsummer Night chased an Insurrectionist freighter, the Kestrel to the Rubble. Keyes took command of the Midsummer Night after his commanding officer, Dmitri Zheng was killed by a traitor of the command crew. He later fought in the Battle of the Rubble, and towed Habitat Exodus to Falaknuma, saving millions of civilians. He was promoted to Commander by Preston Cole for this feat.

He later taught at the OCS Academy. Some of the top brass at HIGHCOM disapproved of him and he got the nickname "Schoolmaster" from those detractors, who thought he didn't belong in command of anything, but a classroom, if that.