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.