This season saw the competition increase to 69 teams from the 42 who took part in 2017–18, thanks to the addition of 26 clubs to the East of Scotland Football League and the return of Wigtown and Bladnoch.
The defending champions were Civil Service Strollers, who beat BSC Glasgow 2-1 after extra time in the final on 20 May 2018.
East Kilbride won 2-1 against Bonnyrigg Rose Athletic in the final to secure the South Challenge Cup for a second time, completing a double with the Lowland League title.
The draw for the first and second rounds took place at the East of Scotland Football Association's AGM on Thursday 7 June 2018.
The four winners from the first round, along with Upper Annandale who progressed after Selkirk withdrew, joined the 59 clubs who received a bye.