The club was established in 2012, after the merger of AO Arta, Aetos Diasello and Omonoia Petra, and is currently competing in the 2nd tier of Greek football, the Super League Greece 2.

In the 2014–15 Football League 2, despite leading the table for a big part of the season, and having the best attacking and defensive record of the group, scoring 60 and conceding just 14, Karaiskakis lost to AO Trikala on the last matchday with a score of 1–2, a result that led to the club missing out on promotion to Beta Ethniki.

On November 5, 2015, after disagreements in a meeting session, former coach, Sakis Papavasileiou, terminated his contract with the club.

Three days later, the club announced the hiring of the 54 year old coach from Arta, Giannis Taprantzis.

On the final day of the first round, Karaiskakis defeated Rigas Feraios 2–1, coming back after conceding in the 42nd minute.

In September 2016, a joint announcement was made with the administration of the Renaissance Arta on the cooperation and common course of the two groups.

In the summer of 2017, HFF initially decided to fill the gap of a team in the 2nd national with the third rounds of the 2016–17 Gamma Ethniki, provided that they will deposit a €300,000 guarantee.

Few seasons after Karaiskakis' establishment, a rivalry against the older club from Arta, Anagennisi, was born.