The Tarkwa based side beat the Kumasi-based side 2-1 in the matchday 21 fixture at the Obuasi Len Clay Stadium.
The Obuasi Len Clay Stadium is now the adopted home ground for the Porcupine following the renovation works on going at the Baba Yara Sports Stadium.
The Porcupines were hoping to revenge the 1-0 defeat suffered against the same opponent in the first round but their effort was not enough on Saturday.
The defeat means Kotoko’s 100% record ( two wins ) at the Len Clay stadium have been broken.
It was Kotoko who drew the first blood on Saturday but Medeama uplifted their game after the goal to win the match.
Emmanuel Gyamfi put the Porcupines ahead after meeting Ibrahim Imoro’s cross in the 13th minute.
However, the Mauve and Yellows, struck twice to overturn the deficit.
First, Prince Opoku Agyemang drew his side level after being teed up by captain Joseph Tetteh Zutah before Richard Boadu scored on the stroke of half time which was enough to carry the day for his outfit.