Already hit by a string of injuries that have forced coach Juergen Klopp to search for another central midfielder, the news could not be worse ahead of the derby with leaders Bayern.
Hummels picked up a heel bone injury in the friendly at Wembley and has been ruled out for the rest of the year while fellow defender Schmelzer suffered a calf muscle injury and will be sidelined for three weeks, Dortmund said on Wednesday.
"Team doctor Markus Braun estimated that Hummels will return to action in mid-January," Dortmund said in a statement.
The club are already without long-time injured midfielder Ilkay Guendogan as well as central defender Neven Subotic, who will be missing for six months with a knee injury.
Defender Lukasz Piszczek has only just returned to training after his own long injury absence following hip surgery.
Dortmund will badly miss Hummels and Schmelzer in the Champions League, with last season's runners-up in third place in Group F and needing two wins in their last two games.
Dortmund's stock price also took a beating after the news, losing more than four percent.
Undefeated Bayern lead the Bundesliga with 32 points from 12 games and a win for the Bavarians, who lost their German Super Cup to Dortmund in July, would put them seven points clear of their biggest domestic rivals who are in second place.
(Reporting by Karolos Grohmann; Editing by Ken Ferris)
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