AAA Mid-Atlantic, Maryland Division, estimates that 554,000 Marylanders will be among those traveling on the highways.
Motorists can expect good driving weather, with sunny skies predicted for Tuesday and Wednesday, and highs in the upper 50s and lows in the 40s, according to the National Weather Service at Sterling, Va.
There is a chance of showers on Thanksgiving day and Friday, with highs in the upper 50s and lows in the 40s.
Travelers can expect traffic on I-95 to be particularly busy, with eight- to 10-mile backups near toll areas, said Buck.
"There will be a little bit of a decrease in truck traffic but there will be more holiday traffic and decreased goods and services available," he said.
Buck said traffic on I-70 in Frederick, Md., should be exceptionally heavy on Wednesday from 3 to 8 p.m.
Traffic on Interstate 81 in Maryland, West Virginia and Pennsylvania also is expected to be heavy.
Construction on Maryland roads will be halted, except for emergencies, from Wednesday through next Tuesday, according to Buck.
The State Highway Administration will use travelers advisory radio reports and message signs to warn drivers of delays or accidents.
Maryland State Police will add patrols in an effort to keep the roadways in Washington County accident-free over the holiday weekend.
Starting at 12:01 Wednesday, troopers will target aggressive drivers, speeders and drunk and drugged drivers in an effort to cut down on wrecks, according to Lt. Bruce Smith, Hagerstown barracks commander.
Police urge travelers to exercise caution and to wear seat belts.
In Maryland, motorists can be stopped for not wearing seat belts.
State Police in West Virginia and Pennsylvania plan increased patrols over the holiday weekend.
"We'll make our presence known," said Cpl. Richard Bosch with the Pennsylvania State Police in Chambersburg.
Police in Pennsylvania will use radar and unmarked cars to cut down on speeders and aggressive drivers, he said.
Bosch said he expects Monday to be particularly hectic since the roads will be filled with holiday travelers returning home, along with hunters heading out for the first day of buck season.
This week is America Buckles Children week, a nationwide campaign to educate motorists in the importance of using child safety seats and having them installed properly.
Along with the recent child safety seat checkpoints conducted jointly with Children's Village of Washington County, state police will be aggressively targeting motorists who don't have their children properly protected in cars, Smith said.
The Thanksgiving holiday weekend officially ends at midnight Sunday, Nov. 29.