In June 2013, the same month as her graduation as a test pilot, Anne “Annimal” McClain was selected by NASA as part of Astronaut Group 21, becoming the youngest astronaut on the NASA roster.

(Above - NASA astronaut and Expedition 58 Flight Engineer Anne McClain is pictured inside the vestibule between the Harmony module and the Destiny laboratory module. She is wearing a sensor on her forehead that is collecting data for the Circadian Rhythms experiment researching how an astronaut's “biological clock” changes during long-duration spaceflight.)

In June 2013, the same month as her graduation as a test pilot, Anne “Annimal” McClain was selected by NASA as part of Astronaut Group 21, becoming the youngest astronaut on the NASA roster. She completed training in July 2015, making her available for future missions. She flew to the International Space Station in December 2018 and returned to Earth in June 2019. On December 9, 2020, McClain was announced as one of NASA’s Artemis astronauts.

For her first spaceflight assignment, McClain was assigned to as flight engineer to ISS Expedition 60/61, scheduled for launch aboard Soyuz MS-13 in June–July 2019, although, in January 2018, NASA astronaut Jeanette Epps was removed from the prime crew of Expedition 56/Expedition 57, resulting in her backup, Serena Aunon-Chancellor taking her place on the flight. Due to this, McClain was moved up to take Aunon-Chancellor's spot on the Expedition 56/57 backup crew, and, in turn, was assigned to the prime crew of Expedition 58/Expedition 59, alongside Russian cosmonaut Oleg Kononenko and Canadian astronaut David Saint-Jacques.

The Expedition 58/59 trio launched aboard Soyuz MS-11 to the International Space Station at 6:32 am ET on December 3, 2018, from the Cosmodrome in Baikonur, Kazakhstan. The launch was originally scheduled for December 20, 2018, but was rescheduled to the earlier date after the failure of Soyuz MS-10 with Expedition 57/58 on October 11, 2018. The crew successfully rendezvoused with the ISS six hours later, spending just over two weeks with the Expedition 57 crew, whose landing had been delayed due to the aborted launch of MS-10.

On March 22, 2019, McClain and Nick Hague performed their first Spacewalk to install the adapter plates while Dextre swaps the batteries between spacewalks. The extravehicular activity (EVA) lasted 6 hours and 39 minutes. They also removed debris from the Unity Module in preparation for the arrival of Cygnus NG-11 in April, stowing tools for the repair of the flex hose rotary coupler and securing tiebacks on the solar array blanket boxes.

McClain was scheduled to perform a second EVA on March 29, with Christina Koch, which would have been the first all-female spacewalk, but spacesuit sizing issues resulted in this EVA's being reassigned to Hague and Koch. McClain conducted a second spacewalk with Saint-Jacques on April 8.

McClain, Saint-Jacques and Kononenko returned to Earth on board Soyuz MS-11 on June 24, 2019.