The clash with England was D'Arcy's 50th Test in tandem with Leinster centre partner Brian O'Driscoll on the international stage.
"Following a scan it was confirmed that D'Arcy has a stress injury to a bone in his foot. The injury will require immobilisation in a boot for at least four weeks, with a projected return to play of six weeks, pending further tests and specialist review," said an IRFU statement.
The D'Arcy injury means Irish coach Declan Kidney will have to make at least five changes to his side from the England game for the trip to Edinburgh to face Scotland this weekend. On top of the injuries to D'Arcy, Zebo, Sexton and McCarthy, prop Cian Healy is suspended after he was cited for stamping on England prop Dan Cole.
Kidney has lost wing Zebo for the rest of the tournament with a broken bone in his foot, outside half Sexton for at leas the Scottish game with a hamstring problem and lock McCarthy for round three with a knee ligament strain.
The injury is bound to hinder D'Arcy's hopes of making a third tour with the Lions this summer, although head coach Warren Gatland knows all about his talent having picked him during his days as Ireland's coach and toured with him in South Africa with the 2009 Lions.