On 23 November 2014, Shkaplerov commanded Soyuz TMA-15M alongside flight engineers Samantha Cristoforetti and Terry Virts (along with three Lego minifigure replicas of them) from the Baikonur Cosmodrome.

Shkaplerov was launched on into space on board Soyuz MS-07 on 17 December 2017, with NASA astronaut Scott Tingle and Norishige Kanai of JAXA.

On 2 February 2018, Shkaplerov and Expedition 54 commander Alexander Misurkin participated in an 8-hour 13 minutes spacewalk outside of the ISS to replace an old electronics box for a high-gain communications antenna.

[10] Shipenko and Peresild returned to Earth on Soyuz MS-18 with Oleg Novitsky, while Shkaplerov became ISS commander as part of Expedition 66.

[11] On 19 January 2022, he participated in an 7-hour 11 minutes spacewalk to configure the Prichal module to support visiting Soyuz and Progress vehicles.

[12] Shkaplerov landed on 30 March 2022 with Russian cosmonaut Pyotr Dubrov and American astronaut Mark Vande Hei.