The president and first lady Melania Trump boarded Air Force One at Joint Base Andrews Friday afternoon.
Trump is bucking tradition by journeying away from North America for his first foreign trek; the past five presidents visited Canada or Mexico as their first venture abroad.
Earlier this month, an administration official portrayed the decision to first visit Saudi Arabia -- home to two of Islam's holiest sites, Mecca and Medina -- as symbolic.
"We thought that was very important because, obviously, people have tried to portray the president in a certain way, but I think that what he wants to do is solve the same problem that a lot of the leaders in the Islamic world want to do," a senior administration official told ABC News.
Pope Francis commented on Trump's visit last weekend, saying that he would not judge the controversial president despite having divergent views on a number of issues, including climate change and immigration.
"I will tell him what I think, he will tell me what he thinks, but I never wanted to judge someone before I listen to the person first," the pope said.
Trump tweeted this morning that the focus of his overseas trip would be on the U.S.
"Getting ready for my big foreign trip," wrote Trump. "Will be strongly protecting American interests - that's what I like to do!"
And first daughter Ivanka Trump, who is joining her father on the trip along with her husband Jared Kushner, posted a photo to her Instagram account of her and Kushner, writing, "Today we embark on this Administration's first foreign trip. I look forward to a historic and meaningful visit to the Middle East and the Vatican in promotion of religious tolerance globally."