The defending champions St Johnstone, who won the 2021 Scottish Cup Final on 22 May 2021,[1] were defeated by Kelty Hearts in the fourth round.

Auchinleck Talbot, Irvine Meadow, Musselburgh Athletic also competed for the first time as SFA members rather than qualifiers.

Clydebank made their first appearance in the Scottish Cup since 2001–02 after re-founding as a junior club in 2003 and gaining their SFA licence.

The draw took place on 24 October 2021 at 5:15pm live on the Scottish Cup YouTube, Facebook and Twitter pages.

The draw took place on 29 November 2021 following the Brechin City v Darvel match live on BBC Scotland.

Auchinleck Talbot were drawn against Premiership club Heart of Midlothian (58 places above them), representing the biggest league position gap between two teams in the competition's history since the pyramid system was introduced.

The draw took place on 22 January 2022 following the Alloa Athletic v Celtic match live on Premier Sports 1.

The draw took place on 14 February 2022 following the Peterhead v Dundee match live on BBC Scotland with guest Paul Slane.

The draw took place on 14 March 2022 following the Dundee United v Celtic match live on Premier Sports 1 with guest Greg Hemphill.