Spanoulis first played pro club basketball with Gymnastikos S. Larissas, and enjoyed a highly successful career start. His skill-set earned him a transfer to Athens and Maroussi, where he won the Greek Basket League's Best Young Player award in 2003. Following an impressive 2004–05 season, during which he helped lead Maroussi to the Greek Basket League's finals and the EuroCup quarterfinals, he moved to Panathinaikos, where he became one of European basketball's major stars. In the 2005–06 EuroLeague season, Spanoulis made his debut in impressive fashion, earning his first All-EuroLeague Team selection as a rookie in the competition. After a stint in the NBA with the Houston Rockets during the 2006–07 season, he returned to Panathinaikos and helped lead them to a EuroLeague title in 2009, being voted the EuroLeague Final Four MVP in the process.