Slayton was scheduled to pilot the second U.S. crewed orbital spaceflight, but was grounded in 1962 by atrial fibrillation, an irregular heart rhythm.

[2]: 17 [note 1] After graduation, Slayton moved to San Antonio, Texas, and entered the Aviation Cadet Training Program.

After completing training, he was assigned to the 340th Bombardment Group, and departed for the European theater of operations on ship from Newport News, Virginia.

[2]: 23–24  After he arrived in Naples, the 340th Bombardment Group moved to San Petrazio, where Slayton flew combat missions into the Balkan Peninsula.

[2]: 26–32 Immediately upon his return to Columbia Army Air Base to serve as a B-25 instructor, Slayton applied and was accepted to fly the new A-26 Invader bomber aircraft.

He graduated with a Bachelor of Science degree in 1949, and accepted a job as an engineer with the Boeing Aircraft Corporation at Seattle, Washington.

[2]: 40–47 While he was a college student, Slayton joined the Air Force Reserve, and was a T-6 Texan pilot flying out of Minneapolis–Saint Paul International Airport.

He transitioned to the Minnesota Air National Guard (ANG), after accepting a demotion from captain to second lieutenant, to allow him to fly the A-26 Invader and P-51 Mustang.

He additionally served as an F-86 Sabre pilot and maintenance officer with the 36th Fighter Day Wing at Bitburg Air Base, West Germany.

After an initial interview at the temporary NASA headquarters in the Dolley Madison House in Washington, D.C., Slayton was psychologically and physically tested at the Lovelace Clinic in Albuquerque, New Mexico, along with fellow future astronauts Scott Carpenter and Jim Lovell.

He moved his family from Edwards Air Force Base to a housing development near Fort Eustis, where he was neighbors with fellow Mercury Seven astronauts Gus Grissom and Wally Schirra.

He received further medical evaluation at Brooks Air Force Base and was diagnosed with idiopathic atrial fibrillation, but he was considered healthy enough to continue flying.

On March 15, 1962, two months prior to the launch of Delta 7, Slayton was medically disqualified from the flight and replaced on the mission by Scott Carpenter.

NASA leadership determined that Slayton was still at risk for atrial fibrillation and removed his eligibility to fly any of the remaining Mercury missions.

[2]: 115–116 [3] Flight doctors recommended a cardiac catheterization to determine if he had a congenital condition, but NASA management rejected the proposal because of the risks of the operation.

[2]: 115–122  In an administrative restructuring in October 1963, Slayton became assistant director of Flight Crew Operations, in addition to his job managing the astronaut office.

[10][2]: 133–140 [11] Slayton continued to be responsible for making crew assignments, and determined the astronauts that would fly on the Gemini and Apollo missions.

[12]: 16–17 [2]: 185, 189  After the fire, Slayton called a meeting of the astronauts from the first groups to be chosen, in April 1967 and announced that they were the candidates for the first lunar landing.

[12]: 346–348  After the postal covers scandal during the Apollo 15 mission, Slayton reassigned the crew to non-flying jobs, effectively ending their astronaut careers.

[12]: 496–497  Slayton supported keeping Joe Engle as the lunar module pilot on Apollo 17, but was pressured by NASA management to replace him with Jack Schmitt, a scientist-astronaut.

[2]: 271 [12]: 450–451 While grounded, Slayton took several measures to attempt to be restored to flight status, including regularly exercising, taking vitamins, quitting cigarette smoking and coffee and reducing his consumption of alcoholic beverages.

[9] After a decade of seeing doctors around the world,[13] in 1971 Slayton was examined at the Mayo Clinic after a long period without heart fibrillation, and was determined to not have a coronary condition.

On July 17, the two craft rendezvoused in orbit and the American astronauts conducted crew transfers with cosmonauts Alexei Leonov and Valeri Kubasov.

At the end of the flight, an erroneous switch setting led to noxious nitrogen tetroxide fumes from the command module's RCS thrusters being sucked into the cabin during landing and the crew was hospitalized as a precaution in Honolulu, Hawaii, for two weeks.

[10] Prior to the ASTP flight, Slayton was assigned by Chris Kraft to manage the Approach and Landing Tests (ALT) of the Space Shuttle program.

The ALT program developed the tests for the Space Shuttle orbiter Enterprise, and modified several F-104 Starfighters and T-38 Talons to train the astronauts.

[1][2]: 306–312 The ALT program ended in late 1977 and Slayton agreed to manage the Space Shuttle's Orbital Flight Tests (OFT).

[1][2]: 310–323 After his retirement from NASA, Slayton served as president of Space Services Inc., a Houston-based company earlier founded to develop rockets for small commercial payloads.

[29] The Slayton biographical exhibit includes his Mercury space suit, his Ambassador of Exploration Award, which showcases a lunar sample, and more.

Although the October 2014, Cygnus CRS Orb-3 mission named the S.S. Deke Slayton was lost when its Antares rocket exploded during launch,[30][31] the Cygnus CRS Orb-4 Orbital ATK space vehicle S.S. Deke Slayton II was successfully launched to the International Space Station on an Atlas V rocket on December 6, 2015.