The trip is the first for retired Marine General James Mattis since becoming Trump's Pentagon chief and is also the first foreign trip by any of Trump's cabinet secretaries.
Officials say the fact that Mattis is first heading to Asia - as opposed to perhaps visiting troops in Iraq or Afghanistan - is meant to reaffirm ties with two Asian allies hosting nearly 80,000 American troops and the importance of the region overall.
That US reaffirmation could be critical after Trump appeared to question the cost of such U.S. alliances during the election campaign. He also jolted the region by pulling Washington out of an Asia-Pacific trade deal that Japan had championed.
"It's a reassurance message," said one Trump administration official, speaking on condition of anonymity.
"This is for all of the people who were concerned during the campaign that then-candidate, now-president, Trump was skeptical of our alliances and was somehow going to retreat from our traditional leadership role in the region."
Trump himself has spoken with the leaders of both Japan and South Korea in recent days and will host Japanese Prime Minister Shinzo Abe in Washington on Feb. 10.
Mattis leaves the United States on Feb. 1, heading first to Seoul before continuing to Tokyo on Feb. 3.
Trump singled out both South Korea and Japan on the campaign trail, suggesting they were benefiting from the U.S. security umbrella without sharing enough of the costs.
In one 2016 television interview, Trump said of the 28,500 U.S. troops deployed to South Korea: "We get practically nothing compared to the cost of this. Why are we doing this?"
Mattis, in his confirmation hearing, appeared to play down those remarks, noting that there was a long history of U.S. presidents and even defense secretaries calling on allies to pay their fair share of defense costs.
But his visit to the region comes amid concerns North Korea may be readying to test a new ballistic missile, in what could be an early challenge for Trump's administration.
Speaking with South Korean Defense Minister Han Min-koo ahead of his trip, Mattis reaffirmed a U.S. commitment to defend the country and "provide extended deterrence using the full range of U.S. capabilities."
Analysts expect Mattis to seek an update on South Korea's early moves to host a Terminal High Altitude Area Defense (THAAD) system, which, once in place sometime in 2017, would defend against North Korea's nuclear and ballistic capabilities.
Still, a South Korean military official played down expectations of any big announcements during the trip, saying Mattis' first visit would likely be "an ice-breaking session" for both countries.
In Tokyo, Mattis is to meet Defense Minister Tomomi Inada, who has repeatedly said Japan is bearing its fair share of the costs for U.S. troops stationed there and has stressed that the alliance is good for both nations.
Japan's defense spending remains around 1 percent of GDP, far behind China, which is locked in a dispute with Japan over a group of East China Sea islets 220 km (140 miles) northeast of Taiwan known as the Senkakus in Tokyo and the Diaoyus in Beijing.
The trip also comes amid growing concern about China's military moves in the South China Sea. Tension with Beijing escalated last week when Trump's White House vowed to defend "international territories" there.
China responded by saying it had "irrefutable" sovereignty over disputed islands in the strategic waterway.
"What U.S. military people say is that considering the pace of China's military build-up such as anti-ship missiles and fighters, there are worries about Japan's capabilities," said a senior Japanese defense ministry official, speaking on condition of anonymity.
Get the latest news delivered to your inbox
Follow us on social media networks