He is regarded among the best Greek goalkeepers of all time having been awarded the most caps in the national team and playing an integral part in the UEFA Euro 2004 triumph.
Nikopolidis made his first steps at his local team of Anagennisi Artas, from which he was transferred to Panathinaikos in the summer of 1989.
He made his debut during the 1990–91 season in a match against his future club, Olympiacos. In his first years as a Panathinaikos player he was a back-up for Józef Wandzik. In 1995, he played five games as Panathinaikos won the championship and three as they retained it the following year. However, it wasn't until the 1997–98 season that he established himself as a regular goalkeeper at the age of 26. In the 2002 Champions league, he helped the club reach the quarter-finals but, in the 2003–04 season, he lost his place to Konstantinos Chalkias when his contract negotiations broke down.
Panathinaikos offered him €400K per year which, although a pay-rise, he thought was not in line with his contributions to the team over the past 15 years nor with his current market value. As he did not immediately accept the offer the management became suspicious and decided to relegate him to the bench for the rest of the 2003–04 season. The Greek sports media and Panathinaikos fans at first took his side in the conflict and criticised president Vardinogiannis.
Just before UEFA Euro 2004, rumours were circulating that Nikopolidis had been approached by arch-rivals Olympiacos. It was discovered later that he had signed an agreement just before the tournament begun earning him €600K per year for three years. After that, the fans' disappointment in him was displayed during the celebrations following the team's 2003–04 season double when Nikopolidis, while raising the trophy, was booed by the majority of the crowd.
Soon after being instrumental in UEFA Euro 2004 helping Greece to lift the trophy, Nikopolidis joined Olympiacos, making an immediate impact for his once rival team. Keeping a clean sheet in the first derby against his former club in the process, he went on to win two Doubles in a row, making him the only Greek player to win three consecutive doubles with two different clubs.
At his new team, Nikopolidis also earned a reputation for making game-winning saves in the most important games. Displaying his penalty-saving abilities, Nikopolidis saved three penalty kicks against Roma, Real Madrid, and Rosenborg BK, making him undefeated from the penalty spot in UEFA Champions League football in the Olympiacos shirt. In the 2007–08 season, he also equaled the Greek league record for the most penalty kicks saved in one season, which included saves against PAOK and former club Panathinaikos. Nikopolidis announced his plans to retire at the end of the 2009–10 season.
However, he took back his decision to stop his career after Sokratis Kokkalis's insistence. The veteran goalkeeper stated that he would delay his retirement for one more year, to retire as champion. He signed an extension on June 16 that will keep him at Olympiacos for the 2010–11 season.
He also took part in the international match "8th Match Against Poverty", on 14 December 2010, in G. Karaiskakis Stadium in Greece, as the UNDP team's goalkeeper.
In January 2011, IFFHS released a list with the best goalkeepers of the first decade, and Nikopolidis was in. He is also in the list with the best goalkeepers of the years 1987-2011.
At 20 March 2011, Olympiacos won the championship, in a 6-0 win against rivals AEK Athens F.C., in G. Karaiskakis Stadium.
He made his final appearance on 17 April 2011 in a home 6-0 victory against Larissa F.C. in G. Karaiskakis Stadium. As a final curtain call, he was replaced by Balázs Megyeri in the last minutes, so he could wave goodbye to the Olympiacos fans.
As the Olympiacos Captain, he was the player to accept the championship trophy, after the match.
He made his debut for the Greece national football team on 18 August 1999 against El Salvador.
He played in the qualifying rounds of the 2002 FIFA World Cup and Euro 2004 where he excelled as Greece qualified for the finals. Nikopolidis was one of the cornerstones of the Greek win in Portugal, where he kept three clean sheets in the knockout stages. He was also voted goalkeeper of the Euro 2004 All Star team.
He became team captain after the retirement of Theodoros Zagorakis.
He has featured in a World XI game in 2002, a rare honour for a Greek player.
Nikopolidis is first among all goalkeepers in the history of the national team with the most caps (90 after his retirement).
On 15 June 2008, Nikopolidis announced his retirement from international football after Euro 2008, claiming that he had made this decision before the tournament started, and also stating that it is about time for a major change in the Greek national squad.
After retirement, he became the assistant manager of Olympiacos in 2012. He was promoted to manager in January 2013 on an interim basis following the firing of Leonardo Jardim. After the arrival of Míchel, he remained in the team as his assistant.
After the end of 2012-13 season, Nikopolidis left Olympiacos, in order to start his career as a head coach.
In 1 October 2015 he was named the manager for the Greece national under-21 football team.As of match played 14 June 2017.
PanathinaikosGreek Championship: 1990, 1991, 1995, 1996, 2004
Greek Cup: 1991, 1993, 1994, 1995, 2004; runner-up (Silver Medal): 1997, 1998, 1999
Greek Super Cup: 1993, 1994; runner-up (Silver Medal): 1996
Olympiacos F.C.Greek Championship: 2005, 2006, 2007, 2008, 2009, 2011
Greek Cup: 2005, 2006, 2008, 2009
Greek Super Cup: 2007
GreeceUEFA European Football Championship: 2004
Greek Best Goalkeeper (8): 1999–00, 2001–02, 2002–03, 2003–04, 2004–05, 2005–06, 2007–08, 2008–09 (Record)
UEFA European Football Championship Team of the Tournament Member: 2004
As Assistant CoachGreek Championship: 2013
Greek Cup: 2013