Winning director set to be named
Scorsese's The Aviator and Eastwood's Million Dollar Baby have been shortlisted for the prize.
Taylor Hackford's Ray, Sideways by Alexander Payne and Marc Forster's Finding Neverland are also nominated.
A DGA win is seen as an indicator for Oscar success, with 50 out of 56 winners taking the Academy Award.
The race for this year's award bears close resemblance for the Oscar nominations for best director - only Forster failed to gain a nod in the category, with Mike Leigh's Vera Drake taking his place.
Scorsese's DGA nomination is the sixth of his career. He has yet to win, but was given a lifetime achievement award from the guild in 2003.
Christopher Reeve
Eastwood said he was "honoured" by his nomination, which he won in 1992 for Unforgiven and went on to scoop the best director Oscar.
Hackford's An Officer and A Gentlemen was nominated in 1982, but it failed to win.
Film-makers Payne and Forster are in the running for the first time.
Directing in television will also be awarded at the ceremony in Los Angeles, with the late Christopher Reeve nominated for his work on The Brooke Ellison Story.
Hit television series Desperate Housewives is in the running for best comedy series, while ER and The Sopranos will jostle for honours in the category for best drama.