On his 18th birthday Werner signed a professional contract until June 2018 with VfB Stuttgart. He went on to score 13 goals in 95 league appearances, during which time he became the youngest player to make 50 Bundesliga appearances in the competition's history. The record was later broken by Kai Havertz in 2018. Stuttgart were relegated in May 2016 which prompted him to join newly promoted club RB Leipzig the following month.
In March 2018, in a match against his former club, Stuttgart, Werner became the youngest player to reach the milestone of 150 Bundesliga appearances, eclipsing the record previously held by Charly Körbel. Later that month he helped Leipzig defeat Bayern Munich for the first time ever when he scored the winning goal in a 2–1 victory. He ultimately went on to score 13 goals and record seven assists for the season.
On 7 October 2018, Werner scored two goals in a 6–0 league win over 1. FC Nürnberg, the first of which was his 50th Bundesliga goal. The result was also RB Leipzig's biggest ever win in the competition. The following month, he scored a twice in a 3–0 league win over Hertha BSC and in doing so recorded the tenth competitive brace of his career. He reached the milestone of 10 league goals for the season on 16 December after scoring twice in a 4–1 win over Mainz 05. His double against Mainz was his fifth brace of the campaign, meaning that by that stage of season every time he scored in a match he went on to score a brace. On 27 January 2019, he made his 100th appearance for RB Leipzig when he started in a 4–0 league win over Fortuna Düsseldorf. He became the first player to score 50 Bundesliga goals for the club on 4 May when he scored once and assisted another in a 3–3 draw with Mainz.
On 4 June 2018, Werner was included in Germany's final 23-man squad for the 2018 FIFA World Cup. He made his first World Cup appearance on 17 June, starting in a 1–0 loss to Mexico in Germany's opening match. He featured in both of the remaining group stage fixtures but failed to score as Germany were eliminated at the first round for the first time since 1938.