The pair picked up injuries in Friday's 2-0 win over Darlington at the Northern Echo Arena.
Guthrie hobbled off early in the game after suffering an ankle problem, and Ferguson didn’t appear for the second half after picking up a leg injury.
Alan Pardew: “It looks like we’ve lost Danny Guthrie and Fergie.
“We really needed those two in the group. That cuts our numbers down – I don’t think they’ll make it.”
Pardew is already without Joey Barton and Nile Ranger, whose applications for work visa were turned down by the United States Embassy in London.
Plus we have two new signings who failed medicals at Liverpool and Stoke, and two players returning from serious injury (Hatem Ben Arfa and Dan Gossling).