At the age of 17, Zisis moved to Athens and to the Greek League team AEK, where he began his professional basketball career.

On June 13, 2007, Zisis signed a 3-year contract worth €5 million euros net income with the Russian team CSKA Moscow.

In 2009, Zisis left CSKA Moscow, and signed a 2-year contract worth €1.6 million euros net income with the Italian League club Montepaschi Siena.

[12] On July 16, 2015, Zisis signed a two-year contract with the German Basketball Bundesliga (BBL) club Brose Bamberg.

In the 2019 German Cup Final, Zisis hit the game-winner, with 2.4 seconds left in the game, to give Bamberg an 83–82 win over Alba Berlin.

[16] On July 15, 2019, Zisis signed a two-year deal with the Spanish Liga ACB club Joventut Badalona.

[21][22] With Greece's under-16 junior national team, Zisis won the silver medal at the 1999 FIBA Under-16 European Championship, and he also led the tournament in scoring.

Zisis also won the silver medal with Greece's under-18 junior national team, at the 2000 Albert Schweitzer Under-18 World Tournament.

In addition, Zisis won the gold medal with the Greek under-20 junior national team at the 2002 FIBA Under-20 European Championship, where he was also named the tournament's MVP.

As a member of the Greek men's national basketball team, Zisis won the gold medal at the 2005 EuroBasket, which was held in Serbia and Montenegro.

At the end of the semifinal game against the French national basketball team, Zisis drove the length of the court, drove into the middle of the floor, drew a double team, and then dished the ball out to Dimitris Diamantidis, who hit a game-winning 3 pointer.

After his great performance at the EuroBasket in 2005, Zisis was named the FIBA Europe Young Player of the Year.

However, in the next game in the tournament, he was hit on the cheekbone and eye socket bone by the elbow of the Brazilian national basketball team's Anderson Varejão.

Even though Greece lost Zisis, who was their leading scorer the year before at the 2005 EuroBasket, they were still able to win the silver medal (including an improbable upset victory over Team USA in the semifinals) during the World Championship tournament.

[25][26] Zisis finished his national team career with Greece, having won a total of ten medals at all levels, eight of which came in FIBA competitions.

[30] Zisis is very close friends with fellow former Greek men's national basketball team players Vassilis Spanoulis, Ioannis Bourousis, and Panos Vasilopoulos.