The 26-year-old, who has 24 goals in 55 appearances for the national team, was taken off in the first half of Leipzig's 4-0 Champions League group-stage win against Shakhtar Donetsk on Wednesday after a knock on the foot in the 13th minute.
"This piece of news is extremely bitter," Germany coach Hansi Flick said. "I feel very bad for Timo personally because he will miss the World Cup which he desperately wanted to play in."
Werner moved back to Leipzig this season after leaving Chelsea in an effort to get more playing time to secure his spot on the World Cup squad.
"A very tough one to take for me! I will be out for the next weeks, will miss the World Cup and will have to support RB Leipzig and Germany from the couch unfortunately," Werner wrote on his social media account. "Thanks for all your messages!"
A very tough one to take for me! I will be out for the next weeks, will miss the World Cup and will have to support @RBLeipzig and @DFB_Team from the couch unfortunately😤😤 thanks for all your messages! pic.twitter.com/umfQKBVi3p— Timo Werner (@TimoWerner) November 3, 2022
He has netted four times in the league so far and scored nine goals in all competitions.
"But especially for the team it is a big loss. We have to make do without an outstanding striker with a high scoring ratio also for the national team and a real team player," Flick said in a statement.
Werner, who was part of the Germany squad at the 2018 World Cup and Euro 2020, was expected to be a member of the squad that coach Flick is due to announce on Nov. 10.
"Scans today in Leipzig showed that he has unfortunately torn the syndesmosis ligament in his left ankle and will therefore be out for the rest of 2022," RB Leipzig said in a statement.
"A decision on his treatment will be made in the coming days."
His injury is a major blow to the Germans, who have struggled to be clinical in the box for some time.
With Werner now ruled out, Flick is almost certain to call up the Bundesliga's leading scorer Niclas Fullkrug, who operates as a natural No. 9, a powerful in-the-box striker.