He began his professional career in 1987 with his local club, Anagennisi Arta, but spent the majority of his career with Panathinaikos (1989-2004) and Olympiacos (2004-2011), winning a combined 11 league titles and nine Greek Cups. But in the summer before he moved to Olympiacos, he manned the posts for Greece during their memorable run at Euro 2004.
They opened the tournament with a 2-1 win over hosts Portugal, then slumped to a 1-1 draw with Spain and a 2-1 loss to Russia. Still, it was enough to finish second in the group and advance to the knockout round, where Greece captured the trophy with three straight shutouts over France (1-0), the Czech Republic (1-0, aet), and--in the final--Portugal (1-0). For his performance, Nikopolidis was named to the UEFA Team of the Tournament.
Nikopolidis went on to captain the national team and amassed a total of 90 caps before his retirement from international football in 2008, enough to rank him sixth on their all-time appearances list and first among goalkeepers.