Pentagon head Mattis has voiced support for the transatlantic alliance, in contrast with the sceptical Trump, and has been tougher on Russia than his boss, whose views worry NATO's eastern European member states in particular.
But the retired marine general is still set to push the rest of the 28-nation group to meet their increased military spending pledges, despite many in Europe facing tough financial situations.
In a sign that the Trump administration's pressure on the issue is bearing fruit, NATO chief Jens Stoltenberg said on the eve of the meeting that boosting spending was a top priority.
"The most important thing is that we increase defence spending and that is exactly what we are doing," Stoltenberg told reporters at alliance headquarters.
The former Norwegian prime minister said the alliance in 2015 had stopped the military budget cuts and last year actually increased spending by 3.8 percent, or $10 billion, but still needs to do more.
Two percent target
Washington has long insisted that NATO members should spend two percent of their GDP on defence, a goal that few meet despite agreeing on it at a summit in Wales in 2014.
On the flight to Brussels for the two-day meeting, Mattis on Tuesday praised the alliance for its enduring help for the United States in Afghanistan.
"This has been the most successful alliance in military history," he said.
He added that the resignation of Trump's national security adviser, Michael Flynn, who quit over behind-the-scenes contacts with Russia, would have "no impact" on America's message to NATO partners.
NATO leaders are expected to meet with Trump for the first time at a summit in Brussels on May 25.
Stoltenberg appeared confident that Trump remains as committed to NATO as his predecessors.
And he downplayed reports of possible tensions within the new US administration, with Mattis and others taking a more traditional line in support of US allies.
"The important thing for me is that the president, the secretary of defence, the secretary of state have all conveyed the same strong message about NATO," he said.
The meeting will also discuss Russia as well as the threat from the Islamic State group.
NATO allies were however looking forward to hearing more about the new administration's position, after a series of contradictory statements from Trump.
"After several months of drifting and waiting for the new US administration, which has sent rather divergent signals, it is important now to have a little clarity," a European diplomat said on condition of anonymity.
As president--elect, in an interview published on January 15 that sent shockwaves through the allies, Trump said the alliance was "obsolete" and had "not bothered about terrorism".
Trump sharply criticised NATO members for defence underspending, but added: "NATO remains very important to me".
In a military career which culminated with him in command of all US forces in the Middle East, Mattis once worked to modernise NATO as Supreme Allied Commander of Transformation.
To the relief of Washington's allies, in his confirmation hearing last month before assuming the civilian defence secretary role, he renewed his commitment to the body.
Stoltenberg is due to make a joint statement with Mattis at 12:55 (1155 GMT), shortly before the full meeting begins.
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