Billy Ogilvie - the manager who led East Kilbride to a dream Scottish Cup tie against Celtic - will leave the Lowland League club on 20 March.
The K Park club say "work commitments" mean the 55-year-old taxi driver cannot perform the role next season.
Ogilvie will leave his post after the East of Scotland Qualifying Cup final against Spartans at Albyn Park.
"The club will now begin the process of finding a replacement manager," said East Kilbride secretary Dave McKenna.
"Over this and last season, Billy has been fully committed to helping the club progress and his efforts and enthusiasm have been outstanding.
"We wish Billy every success for the future and he will always be welcome at EKFC."
Kilby beat Forres Mechanics, Stenhousemuir and Lothian Thistle Hutchison Vale on their journey to a Scottish Cup fifth-round match against Celtic.
The last-16 tie took place at Airdrie's Excelsior Stadium and two scrappy goals by Leigh Griffiths and Colin Kazim-Richards helped Ronny Deila's men progress.
East Kilbride are currently fourth in the Lowland League.
"As happens towards the end of any season, meetings take place in preparation for the new season coming up," said McKenna.
"A major part of this is to secure the services of existing players and discuss what, if any new recruits are needed.
"During these discussions, first-team manager Billy Ogilvie informed the club that due to work commitments he would not be able to continue in post for the new season.
"Billy was very keen to see out the current season and it is to his credit that he was willing to do so. However, he accepts that the club needs to prepare now for the new season.
"This means Billy will remain in post up to the cup final v Spartans on Sunday 20 March."
Ogilvie, who succeeded Iain King in 2014, has three games left as East Kilbride manager. They play BSC Glasgow and Edinburgh City in the league before the cup contest with Spartans.