The 31-year-old suffered a knee sprain on international duty in September when Ghana shared the spoils goalless with Congo in Kumasi, missing Kayserispor's last seven games and the Black Stars’ World Cup qualifiers against Congo in Brazzaville and Uganda.
The former Sunderland striker replaced Guray Vural by the 71st minute while the game stood at a goalless draw, with his side having a numerical advantage following Paul Papp's sending off by the 56th minute.
Gyan tested the hosts' goalkeeper Olexandr Rybka from distance few minutes after coming on before combining with Oleksandr Kucher to set up another chance which was thwarted.
However, Karabukspor took the lead on 77th minute through Gabriel Andrei Torje, after he connected a pass from Ilhan Depe and sent his effort beyond goalkeeper Silviu Lung.
Kayserispor pushed men forward to make their surplus count, but the hosts were resolute at the back to pick their first win in almost two months, handing Gyan's outfit their first defeat in five games.
Kayserispor sit fifth on the log with 14 points, five points behind leaders Galatasaray. Gyan is expected to start next weekend as they host 15th-placed Konyaspor.