It was Scorsese's first DGA award in seven nominations, and it made Scorsese the front-runner for his first Academy Award, Daily Variety reported.
Scorsese came out ahead Saturday night in a field that included Alejandro Gonzalez Inarritu for "Babel," Bill Condon for "Dreamgirls," Jonathan Dayton and Valerie Faris for "Little Miss Sunshine" and Stephen Frears for "The Queen."
The DGA winner has gone on to win the directing Oscar in 52 of the 58 years that the DGA has presented its awards.
Scorsese -- who has never won an Oscar -- received his sixth Academy Award nomination this year for "The Departed." The other Oscar nominees are Frears, Inarritu, Clint Eastwood for "Letters from Iwo Jima" and Paul Greengrass for "United 93."
Scorsese won the Golden Globe for best director last month.