Within a month of leaving Edessaikos, Anastasiadis took over PAOK for the remainder of the 1996–97 season, leading the club to a fourth-place finish in the league with 13 victories in 15 matches, along with a spot in the second qualification round for the 1997–98 UEFA Cup.

After being briefly succeeded by Oleg Blokhin for the 1998–99 Alpha Ethniki season, Anastasiadis returned to PAOK in September 1999 before leaving the following February.

Managing in his first UEFA Champions League, the club finished second after facing Deportivo La Coruña, Hamburger SV, and Juventus in the first group stage.

[2] The next month, Anastasiadis returned to his home town to lead Iraklis for a second time but managed two wins and a draw in the last ten matches of the 2000–01 Alpha Ethniki season to a fifth-place finish.

[8] Cyprus did not qualify for the 2010 FIFA World Cup in South Africa but Anastasiadis led the team to a fourth-place finish that included a 4–1 victory over Bulgaria.

[9] Following his experience in Cyprus, Anastasiadis returned to club management in November 2011 to lead PAS Giannina in the Greek Super League.

[11] The appointment generated controversy as fans expressed their unhappiness due to Anastasiadis's past association with PAOK FC.

"[13][14] With the objective to earn promotion in the 2018–19 UEFA Nations League, Anastasiadis introduced several new players into the squad including Odisseas Vlachodimos, Spyros Risvanis, Manolis Siopis, and Georgios Masouras.

Greece resumed the campaign in November 2018 with a 1–0 victory over Finland but failed to earn a promotion after a 1–0 defeat to Estonia following an own goal from Vassilis Lambropoulos.

In March 2019, Anastasiadis opened the campaign with a 2–0 victory over Liechtenstein before a 2–2 draw with Bosnia and Herzegovina witnessed the team level the score after falling behind by two goals.

[16] Anastasiadis's position came under question following 3–0 and 3–2 defeats to Italy and Armenia respectively, resulting in a public conflict with team captain Sokratis Papastathopoulos.