His skill set earned him a transfer to Athens and Maroussi, where he won the Greek Basket League's Best Young Player award for the 2002–03 season.

In the process, he gained another two EuroLeague Final Four MVP awards, thus joining Toni Kukoč, as the only players in the history of European basketball to achieve that distinction on three occasions.

Maroussi paid Gymnastikos S.Larissas a contract buyout in the amount of 50 million Greek drachmas, in order to secure his player rights.

Following his outstanding season in 2004–05 with Maroussi, Spanoulis signed a 3-year contract worth €1.6 million net income, with EuroLeague powerhouse Panathinaikos Athens.

"[63][64] Rockets [then] Director of Player Personnel, Dennis Lindsey, stated the following about Spanoulis prior to the team signing him.

To sign with the Rockets, and fulfill his dreams of playing in the NBA, Spanoulis took a considerably smaller contract than the one that was being offered to him by his Greek team, Panathinaikos Athens.

"[68] Spanoulis was traded by the Rockets to the San Antonio Spurs, on 12 July 2007, along with a 2009 second-round draft pick, in exchange for center Jackie Butler, and the rights to Argentinian power forward Luis Scola.

[71] Reportedly due to "family reasons," Spanoulis decided that he would not remain in the NBA, with his agent going as far as comparing the Rockets' reluctance to break his contract to slavery.

Spanoulis also claimed that the Rockets' next head coach, Rick Adelman, wanted to keep him, and that both Tony Parker and Gregg Popovich of the San Antonio Spurs were interested in having him on their team.

In game 2 of the 2015–16 Greek League Finals, against Olympiacos' arch-rivals, Panathinaikos, Spanoulis hit a game-winning buzzer-beating 3 pointer.

[94] In game 3 of the Greek League Finals, he scored 11 points in the last 3 minutes and 1 second of the 4th quarter, to seal the victory for his team.

[108] Prior to the start of the 2018–19 season, Spanoulis signed a one-year contract extension with Olympiacos, on 2 July 2018,[109] at a salary of €1.2 million net income.

He passed the previous record holder, Dimitris Diamantidis, in a Greek League game against AEK Athens, in January 2019.

[111][112][113] On 14 March 2019, Spanoulis suffered a season-ending peroneal tendon rupture on his right ankle, in a EuroLeague game against the Italian club Olimpia Milano.

[114][115] After undergoing a 2018–19 season-ending right ankle surgery, for a peroneal tendon rupture, on 1 April 2019,[116] Spanoulis began individual workouts again on 5 July 2019.

On 29 November 2019, Spanoulis passed Juan Carlos Navarro, to become the EuroLeague's all-time career leader in Performance Index Rating (PIR).

He was also congratulated by several EuroLeague players such as: Georgios Printezis, Juan Carlos Navarro, Facu Campazzo, Fernando San Emeterio, Othello Hunter, Šarūnas Jasikevičius, Sergio Rodríguez, Alexey Shved, Kostas Sloukas, Stratos Perperoglou, Ante Tomić, Toko Shengelia, Vasilije Micić, Vladimir Lučić, Gustavo Ayón, Nick Calathes, Jordan Taylor, Kyle Hines, and Kostas Papanikolaou.

[156][157][158][159][160] At Spanoulis' jersey retirement ceremony, he was paid tribute by several well-known EuroLeague players, among them: Kostas Papanikolaou, Kyle Hines, Nigel Williams-Goss, Nikola Milutinov, Nikola Mirotić, Kostas Sloukas, Panagiotis Giannakis, Milan Tomić, George Bogris, Dimitris Diamantidis, Sasha Vezenkov, Georgios Printezis, Nick Calathes, Rasho Nesterovic, Shaq McKissic, Moustapha Fall, Thomas Walkup, Nikos Chatzivrettas, Sofoklis Schortsanitis, Lazaros Papadopoulos, Dimos Dikoudis, Argyris Kampouris, Pero Antić, Joe Arlauckas, Dejan Bodiroga, Daniel Hackett, and Nikos Galis.

Spanoulis was also paid tribute at his jersey retirement ceremony, by several EuroLeague basketball coaches, such as: Ettore Messina, Dimitris Itoudis, Jonas Kazlauskas, Vangelis Angelou, and Georgios Bartzokas.

Vassilis has done things that are difficult for anyone to predict, although from a young age – because I was his supporter in his early days – he was a player who had passion and faith, worked hard, and he listened to advice that would help him reach higher.

Kudos to the people who realized that this had to be done, for a player who started modestly, far from the center of basketball, and began to compete with the best in the world, and to make us rejoice with his successes.

Every day that he was on the court, he gave his best, and he wanted to make his goals come true...These players [current players] need to understand that talent is not enough, and that you must understand the game, but also work hard, because without hard work, you will not achieve even 1/10 of what Vassilis did.”Spanoulis was a key member of the Greek under-18 junior national team at the FIBA Under-18 EuroBasket's 2000 tournament.

[173] Spanoulis also played at the 2000 edition of the Albert Schweitzer Under-18 World Tournament, where he averaged 14.0 points per game,[174] and won the silver medal with Greece.

Spanoulis was also on the Greek under-20 junior national team that finished in first place, and thus won the gold medal, at the 2002 FIBA Under-20 EuroBasket.

Greece finished in 5th place in the tournament, losing to Manu Ginóbili and the eventual gold medal-winning Argentine national basketball team, 69–64, in the quarterfinals.

Spanoulis averaged a team-leading 12.8 points per game,[187] at the 2008 FIBA World Olympic Qualifying Tournament, where Greece finished in first place.

[197] It was just the second time in Greece's history, that the senior men's national basketball team won the gold medal at the FIBA EuroBasket, and the first time since the 1987 FIBA EuroBasket, when the legendary players Nikos Galis, Panagiotis Fasoulas, Fanis Christodoulou, and Panagiotis Giannakis, led Greece's national team.

Spanoulis was the game's leading scorer, with 24 points, and he also dished out 5 assists,[200] but Spain got the win, by a score of 82–77, over the depleted Greek squad.

He can be walking next to you, and in those two minutes, you're getting so much energy, and so much knowledge, in two minutes.”On 27 November 2024 AS Monaco Basket of the LNB Pro A and EuroLeague signed Spanoulis as their new head coach with a two-year contract.

[244] Over his playing career in Europe, some of the basketball players that he has been friends with have included: Batiste,[245] Parker, Arroyo, Jasikevičius, Teodosić, Nesterović, Blakney, Calathes, Bourousis, Diamantidis, Papaloukas, Printezis, Vasilopoulos, James, Larkin, Mantzaris, Papapetrou, Sloukas, Papanikolaou, Agravanis, Perperoglou, Vezenkov, Milutinov, Tomić, Antić, Vukčević, Hines, Hunter, McKissic, along with numerous other teammates that he is also good friends with from his basketball playing career.