The reigning champions were Connah's Quay Nomads.
[1] The game between Port Talbot Town and Swansea University was postponed on 16 July after two Port Talbot players tested positive for COVID-19 and the Port Talbot squad was told to self-isolate by Welsh health authorities.
[2] Port Talbot Town subsequently forfeited the match in line with the approach adopted by the Football Association of Wales for the 2021–22 season's cup matches in relation to teams unable to play cup games due to Coronavirus infections.
The tie between Llandudno and Connah's Quay Nomads was reversed with Connah's Quay Nomads hosting the game instead of Llandudno.
The draw for the Third round took place on 11 August 2021.