In 2011, Ryzhikov served as cavenaut into the ESA CAVES[8] training in Sardinia, alongside Thomas Pesquet, Tim Peake, Norishige Kanai and Randolph Bresnik.

In 2016, Ryzhikov served as backup Commander of the Soyuz TMA-20M mission, backing up Russian cosmonaut Aleksey Ovchinin as flight engineer for ISS Expedition 47/48,[9] following the launch of Soyuz TMA-20M 19 March 2016, Ryzhikov was assigned to the prime crew of ISS Expedition 49/50 as a flight engineer.

[citation needed] Ryzhikov was assigned as Commander of the Soyuz MS-02 spacecraft, he and his two crewmates, Roscosmos cosmonaut Andrei Borisenko and NASA astronaut Shane Kimbrough were originally scheduled to launch on 23 September 2016 and dock to the ISS two days later, although the launch was delayed indefinitely due to technical issues with the Soyuz spacecraft.

[10] Ryzhikov and his two crewmates finally launched on 19 October 2016 and successfully docked with the ISS two days later, joining the Expedition 49 crew alongside Russian cosmonaut Anatoli Ivanishin, JAXA astronaut Takuya Onishi and NASA astronaut Kathleen Rubins.

[11] Originally the Expedition 49 crew were scheduled to work together as a six-person crew for two months, although due to the lengthy delay with the launch of Soyuz MS-02, Expedition 49 only spent about one week as a six-person increment, with Ivanishin, Onishi, and Rubins returning to Earth on 30 October 2016.

Ryzhikov launched from Baikonur on October 14, 2020, alongside Russian cosmonaut Sergey Kud-Sverchkov and NASA astronaut Kathleen Rubins.