Nationwide, TSA is expecting to screen close to 3 million people on Wednesday alone, so make sure to arrive at the airport with plenty of time before your flight.
Also keep an eye on your flight status, especially if you're traveling to the Midwest, where an arctic blast could disrupt travel over the next few days. If you're heading to the East Coast, wet weather could also cause some delays.
If you're hitting the road, prepare for traffic. The Automobile Club of Southern California is predicting more than 6 million Californians will travel more than 50 miles to their destination.
Wednesday will be the worst day to travel by car , with the afternoon hours being the busiest. If you're heading north up the 5 Freeway, beware. Traffic time is expected to double to almost 4 hours between Los Angeles and Bakersfield.
However, it should be smooth sailing on freeways come Thanksgiving Day, according to transportation analytics company INRIX.
On the return home, the best travel times for motorists are before 1 p.m. on Sunday, and before 8 a.m. or after 7 p.m. on Monday, the company said.
The Associated Press contributed to this report.