A player comfortable at right back or in midfield, Paintsil had stints in his native Ghana with Berekum Arsenal and Liberty Professionals and a brief spell with Polish side Widzew Łódź before moving to Israeli club Maccabi Tel Aviv in 2002.
Pantsil joined Israeli club Maccabi Tel Aviv in 2002, where he was a member of the team that won both the Israeli title and reached the Cup semi-final. He made 46 league appearances and five appearances in the Champions League.
In December 2004, he transferred to rivals Hapoel Tel Aviv helping them to second place in the league in 2006 and to win the Israeli State Cup in May 2006. He made 42 appearances for Hapoel, scoring three goals.
After the 2006 World Cup, Israeli international Yossi Benayoun recommended Paintsil to West Ham United manager Alan Pardew as the Premier League club was in need of a right-back. Pardew took Pantsil with the rest of the squad on their pre-season tour of Sweden. Impressive performances by Paintsil during West Ham's Swedish tour allowed him to gain favour with Pardew. In August 2006, West Ham completed the signing of Paintsil after a work permit was granted. Paintsil was given the number 14 shirt at West Ham and competed for a place in the side with Tyrone Mears and Jonathan Spector. He made only five appearances for West Ham during the 2006–07 season and in the summer of 2007 was weighing up his options in order to ensure his place in the Ghana national team for the 2008 Africa Cup of Nations. However, the defender remained at West Ham and in July 2008, with the majority of his 24 games for West Ham being substitute appearances, Paintsil was given permission to speak to Fulham with a view to a move.
On 15 July 2008, Paintsil and teammate Bobby Zamora completed their moves to Fulham for a combined transfer fee of £6.3 million. He became a first team regular during the 2008–09 season, helping the Cottagers to a record seventh-place finish. His performances improved as the season progressed and he retained a regular starting place in the 2009–10 season. In June 2011 new Fulham manager Martin Jol announced that Pantsil had played his last game for Fulham and that he would not be returning for the 2011–12 season. He was released by Fulham in June 2011.
On 21 July 2011, Paintsil joined Leicester City on a free transfer. He became manager Sven-Göran Eriksson's eighth signing of the summer. Paintsil was released by Leicester in May 2012 having made seven appearances in all competitions. He had made no appearances since the appointment of new Leicester manager, Nigel Pearson in November 2011 and had not played for Leicester since October 2011.
On 12 August 2012 Paintsil returned to Israel by signing at Hapoel Tel Aviv for one season.
Paintsil joined Santos in the National First Division on 10 October 2013 after failing to agree terms with Premier Soccer League team Polokwane City.
On 8 July 2014 Paintsil joined Maritzburg United. On 29 January 2016 he was released by Maritzburg United, following a falling out with manager Ernst Middendorp on disciplinary grounds together with teammate Ashley Hartog.
On 24 June 2016, Paintsil retired from football.
On 27 June 2016, Paintsil became the new assistant manager at Kaizer Chiefs.
Paintsil was a member of the Ghana Under 21 team who were runner-up in the FIFA World Youth Championship in Argentina in 2001 and played for the senior team in the African Cup of Nations in Mali in 2002 and Egypt in 2006. He was also a member of the Ghana 2004 Olympics football team who exited in the first round in Greece, having finished in third place in Group B. Paintsil played in all the matches of Ghana's national team in the 2006 World Cup finals, where Ghana were beaten by Brazil in the second round.
Following the first and second goals in Ghana's 2–0 victory over the Czech Republic on 17 June 2006, he celebrated by waving an Israeli flag, he also waved as the final whistle blew. This action provoked some protests in his native country Ghana and the Arab world. Afterwards the Ghanaian Football Association issued an apology, and said of Pantsil "He was naive". He was a member of the Ghanaian 2010 World Cup team that reached the quarter-finals in South Africa before losing to Uruguay. He played in all five games. On 13 June 2010, in a World Cup group-stage match against Serbia, another variation of his name appeared on his jersey, Panstil.
Paintsil's family has reportedly received repeated threats to their lives in Ghana. His younger brother Mark fled to Israel on a tourist visa. His visa expired and he was jailed whilst applying for political asylum pending immigration status decisions. According to Mark, the rest of the family is in Britain and cannot go back to Ghana. He was quoted as saying "I cannot return to Ghana because I truly fear for my life. My sister, after returning to Ghana, joined my brother and parents in London immediately, and now I am in prison and there is nothing I can do." John is also famous for his lap of honor at home matches, he sometimes only wears one sleeve on his left arm in the winter, leaving his right arm bare by simply cutting off the other sleeve, the reason why is unknown.Maccabi Tel Aviv
Israeli Premier League Winner 2002–03
Hapoel Tel Aviv
Israel State Cup Winner 2006
UEFA Europa League runner up 2009–10
Africa Cup of Nations Bronze Medal: 2008
FIFA World Cup last 16: 2006
FIFA World Cup 2010: Quarterfinals