Jan Kirchhoff has been ruled out for up to eight weeks with a hamstring injury.
The German midfielder suffered the strain in the 1-1 draw with West Bromwich Albion at the weekend.
It is the latest setback for manager David Moyes, who has yet to win a Premier League game this season.
A club statement said: "Jan Kirchhoff has been ruled out for a minimum of six weeks after suffering a hamstring injury during Sunderland's draw against West Bromwich Albion.
"The former Bayern Munich player was stretchered off in Saturday’s game at the Stadium of Light, and in order to assess the extent of the injury the 26-year-old underwent a scan which revealed he will be out for six to eight weeks.
"The midfielder will now focus on returning to action as soon as possible."