Florian Wirtz will be sidelined "for several months" after tearing knee ligaments as Bayer Leverkusen lost 1-0 at home to Cologne Sunday while elsewhere in the Bundesliga, Erling Haaland made his long-awaited return from injury for Dortmund.
Wirtz, 18, tore the anterior cruciate ligament in his left knee during a first-half challenge in Leverkusen's derby defeat.
He was stretchered off in clear distress.
The attacking midfielder "will be out for several months", Leverkusen said in a statement.
Wirtz misses Germany's friendlies against Israel and the Netherlands later this month and faces a race against time to be fit for the World Cup in Qatar which kicks off in November.
Wirtz's injury capped a bad day for Leverkusen as Cologne's Kingsley Schindler came off the bench to volley in a superb second-half winner for his first Bundesliga goal.
The loss of Wirtz is a serious blow to Leverkusen with their top-scoring Czech striker Patrik Schick already sidelined by a torn calf.
Leverkusen are third in Germany's top flight, but suffered a second defeat in three days after losing to Atalanta in their Europa League last 16, first-leg tie on Thursday.
Cologne are seventh as Steffen Baumgart's visitors out-thought and out-muscled Leverkusen.
The hosts lost three players in the first half of a bruising derby as defenders Jeremie Frimpong and Odilon Kossounou also suffered leg injuries.
Haaland made his first appearance since late January as Dortmund closed the gap to Bundesliga leaders Bayern Munich with a 1-0 home win over Covid-hit Arminia Bielefeld.
Haaland came on for the last half hour at Signal Iduna Park after Marius Wolf's first-half winner against Bielefeld who had six players and head coach Frank Kramer out with Covid.
Dortmund were also missing defenders Mats Hummels and Raphael Guerreiro who also tested positive for the coronavirus last week.
The home win allowed Dortmund to trim Bayern's lead to seven points after the league leaders were held to a 1-1 draw at Hoffenheim on Saturday.
Dortmund have a game in hand and can reduce the deficit further on Wednesday when they travel to Mainz.
There was more good news for Dortmund as teenage US international Giovanni Reyna also made his return from injury with a brief cameo.
Japan midfielder Daichi Kamada scored the winner as mid-table Eintracht Frankfurt came from behind to seal a 2-1 win at home to Bochum.
RB Leipzig climbed back into the Champions League spots as they came from behind to hand bottom side Greuther Fuerth a 6-1 home thumping.
Fuerth took a shock early lead, but Leipzig roared back to take a 4-1 halftime lead with goals by Andre Silva, Emil Forsberg, Konrad Laimer and Benjamin Henrichs.
Second-half goals by French pair Mohamed Simakan and Christopher Nkunku completed the rout as Fuerth remain on course to be relegated.