It was the second time that Medeama, founded in 2002 has beaten the Porcupine Warriors to the knockout title, after a similar feat in 2013.
The one-off match was for the first time held outside the Ghanaian capital, Accra, with the harbour-city, Sekondi hosting it.
Medeama went up after 39 minutes through Kwasi Donsu before Ivorian-import Ahmed Toure drew level for Kotoko just before the break.
Substitute Bismarck Oppong scored the winner on the hour-mark as the ‘Mauves and Yellow’ cruised to the title, and a place at next year’s CAF Confederation Cup.
Medeama reached the 1/8th round on their maiden continental campaign two years ago in the second-tier continental club championship.