He arrived at the ISS aboard Soyuz TMA-01M on October 9, 2010, and served as a flight engineer until he took over command of the station on November 25, 2010, at the start of Expedition 26.

[18]: 40–41  After his first year, Kelly transferred to State University of New York Maritime College, where he received a Naval Reserve Officers Training Corps (Navy ROTC) scholarship.

During the summer after his first year, Kelly sailed aboard SUNY Maritime's training ship, Empire State V, and stopped in Mallorca, Hamburg, and London.

He completed his initial flight school at NAS Pensacola, where he flew the T-34 Mentor propeller driven trainer plane, after which he was selected to fly jets.

Upon completion of this training in September 1990, he was assigned to VF-143, and deployed to the North Atlantic and Persian Gulf aboard the aircraft carrier USS Dwight D.

His classmates included his brother, Mark, and other future astronauts Alvin Drew, Lisa Nowak, and Stephen Frick.

[18]: 166–170 After attaining the rank of captain in the U.S. Navy, Kelly retired from active duty on June 19, 2012, after 25 years of naval service.

[11] In September 2002, Kelly served as the commander of the NEEMO 4 mission aboard the Aquarius underwater laboratory, 4 mi offshore from Key Largo.

The NEEMO 4 crew spent five days saturation diving from Aquarius as a space analog for working and training under extreme environmental conditions.

[22] In March 1999, Kelly was assigned to STS-103 as a pilot aboard Discovery, under command of Curt Brown, on a mission to install new instruments and upgraded systems on the Hubble Space Telescope (HST).

The STS-103 mission specialists conducted three EVAs to replace gyroscopes and a transmitter, and to install a new computer guidance sensor and recorder.

Endeavour's crew successfully added a truss segment, an external spare-parts platform, and a control moment gyroscope and to the ISS.

The mission was extended to 14 days while testing a new system that enabled docked shuttles to draw electrical power from the station.

[18]: 262–263 [25] Kelly lifted off aboard Soyuz TMA-01M from the Baikonur Cosmodrome in Kazakhstan at 7:10 pm EDT on October 7, 2010, along with cosmonauts Aleksandr Kaleri and Oleg Skripochka.

[26] TMA-01M was the first launch of an updated model of the Soyuz spacecraft, and featured improved guidance, environmental control, and flight-control systems.

[27][28] Kelly, Kaleri, and Skripochka arrived at the ISS on October 9, 2010, and joined Commander Douglas H. Wheelock and flight engineers Shannon Walker and Fyodor Yurchikhin on Expedition 25.

[25] The crew of Expedition 24/25 returned to Earth on November 25, 2010, aboard Soyuz TMA-19; Wheelock transferred command of the station to Kelly.

Soyuz TMA-01M landed in Kazakhstan on March 16, 2011, and Kelly traveled to TIRR Memorial Hermann in Houston to see Giffords and Mark.

The primary goal of the year-long expedition aboard the orbiting laboratory was to better understand the effects of spaceflight on the human body.

[35] In November 2012, Kelly was selected for a one-year mission to the ISS, but was medically disqualified the following day due to his vision worsening in microgravity.

[18]: 309–312 Kelly, Kornienko, and Gennady Padalka launched aboard Soyuz TMA-16M spacecraft from the Baikonur Cosmodrome in Kazakhstan at 3:42 pm EDT on March 27, 2015.

Once aboard, the crew performed scientific experiments, including evaluations of the fluid shifts in their bodies to determine their effects on eyesight, and repeated collections of blood and urine for chemical analysis.

[38] During Expedition 43, the ISS received supplies from the SpaceX Dragon CRS-6 mission, but lost their resupply due to the failure of the Russian Progress 59 spacecraft.

[50][51] On October 28, 2015, Kelly and Lindgren performed an EVA to service the Canada Arm 2, the Alpha Magnetic Spectrometer, and to install cables for the International Docking Adapter for the Boeing CST-100 Starliner and SpaceX Crew Dragon spacecraft.

[56] On December 21, 2015, Kelly and Kopra performed an unscheduled EVA to release the brake handles on the Mobile Transporter rail car for the Canada Arm 2, which had unexpectedly stopped when it was remotely commanded by the flight controllers.

[61] On March 1, 2016, Kelly transferred command of the ISS to Kopra, and returned to Earth alongside Korniyenko and Volkov aboard Soyuz TMA-18M.

[62][63] In addition to the biological tests conducted on all astronauts on the station, Kelly also participated in comparative study on the effects of spaceflight with his identical twin Mark as the ground control subject.

[77] Kelly and Lt. General Mark Hertling, United States Army (retired), tweeted instructions for Russian soldiers to sabotage their T-72 main battle tanks.