After spending time at VK Tielrode and Germinal Beerschot, Vertonghen moved to the Netherlands and signed a contract with the youth academy of Eredivisie side AFC Ajax. He began as a midfielder but then became a regular at centre-back for Ajax. During his time in the reserves, he became known for an incident in a 2006 KNVB Cup game against Cambuur Leeuwarden, his first home game at the Amsterdam Arena, where he scored a goal to put Ajax 3–0 up. He had attempted a back pass to the Cambuur goalkeeper while a teammate was receiving treatment but instead the ball went into the goal. Since it was unintentional, Ajax allowed Cambuur to score a goal in return. On 23 August 2006, Vertonghen made his first team debut in the Champions League third qualifying round against Copenhagen. He made his first start and Eredivisie debut in a 6–0 win over Willem II at the Amsterdam Arena and would play another two matches for the first half of the season.

Vertonghen made his international debut at the under-21 level in 2006 and played in the 2007 UEFA U21 Championships.

On 2 June 2007, he made his senior debut for the national team in a 2–1 home loss against Portugal in UEFA Euro 2008 qualification. At the end of the game he was fouled by substitute striker Hugo Almeida, who was sent off. Vertonghen was also selected for the 2008 Olympics and played in every match as the Belgians unexpectedly took fourth place.

Vertonghen returned to Ajax for the 2007–08 season, where he was tipped for stardom, but was unable to break through due to a severe injury and the presence of central defenders John Heitinga and Thomas Vermaelen. Johan Cruyff had made no secret of his admiration for the left-footed youngster who can handle any left-sided position in defence and midfield, opting, on 26 September 2008, to extend his contract to 30 June 2013.

In the 2010 World Cup qualifying, he began to establish himself as a regular, initially at centre-back as former Ajax teammate Thomas Vermaelen’s partner. He scored the opening goal, also his first ever international goal, in an August 2009 friendly against the Czech Republic that ended in a 3–1 loss. On 7 September 2009, in a World Cup qualifying away match against Spain, he injured his toe and had to be stretchered off and substituted in the 29th minute. The match ended bad as well; a 5–0 loss. Now he usually plays as leftback as Vermaelen and Vincent Kompany are the preferred pairing in central defence. He was back in the starting eleven for the friendly against Hungary, a 3–0 win and the 1–0 loss to Croatia the following March.

Vertonghen stated on numerous occasions late in the 2010–11 season that he was considering leaving Ajax at the end of that season. In May 2011, Frank de Boer confirmed Manchester City boss Roberto Mancini was present at the 2011 KNVB Cup Final held on 7 May 2011, where Vertonghen’s side lost 3–2 to Twente. Mancini was reportedly scouting Vertonghen to strengthen his side after they had qualified for the UEFA Champions League 2011–12 campaign.

Throughout the 2011–12 season, Vertonghen was linked with English club Tottenham Hotspur and publicly expressed his desire to make the move to White Hart Lane ahead of numerous other teams. A key factor in this was his desire to play as a centre-back, with Arsenal wanting to use him as a defensive midfielder. On 8 July 2012, Tottenham agreed a fee and terms for Vertonghen subject to a medical. On 12 July, Tottenham announced that they had officially completed the signing of Vertonghen, for an amount around 12 million Euros, after he successfully completed his medical. Vertonghen took part in his first game as a Tottenham player in a 3–2 friendly win against Brentford on 14 July, then later scored his first goal for the club on 26 September in a 3–0 win against Carlisle United in the third round of the Football League Cup.

Vertonghen scored his first Premier League goal against Manchester United in a historic 2–3 win at Old Trafford, although this was later ruled to be an own goal by Jonny Evans. He scored in the league for Tottenham on 16 December, the only goal of the game, in a win at White Hart Lane against Swansea City. Vertonghen then scored a brace in a losing effort against Liverpool on 10 March. He was named Premier League Player of the Month for March 2013, making himself the second Belgian and the 12th Spurs player to win the award. On 11 April 2013, Vertonghen was sent-off against Basel during Tottenham’s Europa League quarter-final second leg. Tottenham went on to lose the tie 4–1 on penalties after a 4–4 draw on aggregate. Vertonghen was named in the 2012–13 PFA Team of the Year, alongside Rio Ferdinand, Leighton Baines and Pablo Zabaleta in defence.

On 13 May 2014, Vertonghen was named in Belgium’s squad for the 2014 FIFA World Cup. In the team’s opening match against Algeria, the African side was awarded a penalty after Vertonghen pulled down Sofiane Feghouli and received a yellow card. Feghouli scored for Algeria from the penalty spot, but Belgium came back to win 2–1. He was then replaced by Thomas Vermaelen in the starting line-up for the second match against Russia on 22 June. After 31 minutes, however, Vermaelen was taken off with an injury and replaced by Vertonghen. In the final group match, Vertonghen captained the team and scored the winning goal as Belgium beat South Korea 1–0.

At the start of the 2014–15 season, Vertonghen appeared to be out of favour with new manager Mauricio Pochettino. The Argentine gave Vertonghen limited games, preferring Younès Kaboul and Federico Fazio. However, Kaboul lost his place to Vertonghen, who formed an effective partnership with Fazio. Together, the pair, over the span of 15 games, celebrated 11 wins and only suffered one loss. Vertonghen helped Spurs to reach the 2015 League Cup Final and started the game on 1 March 2015, but Tottenham lost to rival club Chelsea at Wembley Stadium 2–0.

Vertonghen was joined in defence by former Ajax teammate and compatriot Alderweireld at the start of the 2015–16 season. Over the first ten games of the season, Vertonghen and Alderweireld played ten out of the opening ten games together, with Spurs suffering only one loss during the span. In late January 2016, he damaged his medial knee-ligament and did not play for 11 weeks. He returned in the home match against Manchester United on 10 April 2016, which finished in a 3–0 win, the first home league win for Tottenham against Manchester United since 2001. His partnership with Alderweireld in the defence was recognised as being crucial for the club which had the joint-lowest number of goals conceded in the Premier League that season.

On 2 December 2016, Vertonghen signed a new contract with Tottenham until 2019. However, in mid January 2017, Vertonghen suffered an ankle ligament injury that would see him out of action for five weeks. He returned to the team on 19 February in the fifth round FA Cup match against Fulham at Craven Cottage. This season, Vertonghen was part of the Tottenham defence that achieved the best defensive record for the club, with only 26 goals conceded in the Premier League (and only 9 conceded in home league games), 6 better than the previous record of 32 conceded that was set in the 1908–09 season in the Second Division. He was considered then one of the best defenders in the Premier League.

Early in the 2014–15 season, Vertonghen knocked a child unconscious with a misplaced shot during a training session with the Belgian squad. In 2016, he injured two ligaments in his ankle in an accident while training before the quarter-final against Wales during UEFA Euro 2016, and as a result missed the match that Belgium lost.

On 7 January 2018, Vertonghen scored his first goal for the club since October 2013, a 30-yard strike in the 3–0 win over Wimbledon in the third round of the 2017–18 FA Cup. This season, he made 36 appearances out of the 38 Premier League games, as well six in the UEFA Champions League, and five in the cups.

In the opening game of the 2018–19 season against Newcastle United, Vertonghen scored Tottenham’s first goal of the season 8 minutes into the game, helping the team to a 2–1 win. However, he suffered a hamstring injury in the game against Huddersfield on 29 September, and was out for two months, returning to the starting lineup in the Champions League game against Inter Milan in late November. His contract with Tottenham was extended to 2020 in December 2018. In the last 16 round home game against Borussia Dortmund in the Champions League, Vertonghen played in the less familiar position of left wing back, scoring one goal and providing one assist in a game that finished 3–0. He received wide praise for his performance in this game, and he was named the Champions League Player of the Week by UEFA. In the match against Ajax in the semifinal of the Champions League, he suffered a head injury after clashing his head with Toby Alderwiereld, but returned to play in the leg in Amsterdam wearing a protective mask, and helped the team to a dramatic win against Ajax that sent Tottenham to their first Champions League final.

At the 2018 FIFA World Cup in Russia, Vertonghen initiated the scoring in Belgium’s second-half comeback from a 0–2 deficit against Japan, heading from 20 yards out to the far post in a 3–2 comeback victory.

In the 2019–20 season, Vertonghen scored a late goal also as the winning goal, his first of the season, in the away game against Wolverhampton Wanderers to snatch a 2–1 win. On 26 December 2019, he made his 300th Tottenham appearance in a 2–1 home comeback win over Brighton & Hove Albion. Vertonghen’s contract was originally set to expire on 30 June 2020, but was extended to the end of the 2019–20 campaign due to the stoppage related to COVID-19. He became a free agent after the club’s last game of the season against Crystal Palace.

On 14 August 2020, Benfica announced the signing of the 33-year old on a three-year deal. He made his debut on 15 September away to Greece’s PAOK FC in the third qualifying round of the Champions League, a 2–1 loss in a one-leg match where he scored an own goal. Three days later he played for the first time in the Primeira Liga, a 5–1 win at F.C. Famalicão in the season opener.