Macedonia has set Sept. 30 for a referendum on the government's deal in June with neighboring Greece to change its name to the Republic of North Macedonia which would largely clear the path for it to join NATO and the European Union.
Mattis is the latest in a string of Western leaders, including German Chancellor Angela Merkel, to visit Skopje and urge it to embrace the deal.
"We're just looking at how do they shape their own future... not shaped by someone else," Mattis told a small group of reporters en route to Skopje.
"We do not want to see Russia doing there what they have tried to do in so many other countries," Mattis said, adding that Moscow's interference concerned him.
In July, Greece expelled two Russian diplomats and barred two other people from entering the country for trying to bribe officials and foment demonstrations to thwart the deal to allow Macedonia to join NATO.
Russia flatly denied the allegations and responded in kind with expulsions of Greeks.
Mattis, who will be in Skopje for only a few hours, is expected to meet with the country's prime minister and defense minister as well as President Gjorge Ivanov, who opposes the deal.
Washington believes that pro-Russian groups are actively working to undermine the referendum, with Moscow trying to buy off individuals and spreading disinformation.
"No doubt that they have transferred money and they are also conducting broader influence campaigns," Mattis said. He said it was unclear how effective Moscow's efforts had been.
Moscow's ambassador to Skopje has criticized Macedonia's ambitions to join NATO, saying it could become "a legitimate target" if relations between NATO and Russia deteriorate further.
NATO invited Macedonia to begin accession talks with the alliance, but said it would have to change its constitution and adopt the new name first. The EU has also said it would set a date for Macedonian accession talks pending implementation of the name deal.
Greece, a member of both NATO and the EU, has refused to accept the Balkan country's name, saying it implies territorial claims on the Greek province of Macedonia.
Despite U.S. President Donald Trump portraying NATO as an alliance in crisis, recent opinion polls show that more than 50 percent of people are likely to vote, with the majority supporting the membership bids and the name deal.
Several thousand Macedonians gathered in the capital Skopje on Sunday to express their support for NATO and European Union membership bids and for a change in the country's name.
Russian 'disinformation'
Washington is concerned that Russia is spreading disinformation ahead of the referendum with the aim of suppressing voter turnout and creating an impression that the United States is not committed to the region.
Prime Minister Zoran Zaev's government pushed for an agreement with Greece, which nationalists have opposed, saying it is against the constitution.
"Our approach to disinformation is not to try to counter every single argument... we show by our senior-level visits, our presence, we show by highlighting our cooperative activities," Laura Cooper, deputy assistant secretary of defense for Russia, Ukraine and Eurasia, said.
The United States spends nearly $5 million a year in security assistance towards Macedonia and since 1991 has provided about $750 million in total assistance. Macedonia has a few dozen troops in Afghanistan as part of the NATO-led mission.
U.S. officials believe Russia accelerated its disinformation campaign in southeast Europe in 2014, the same year it annexed Crimea from Ukraine.
"What is in some ways frustrating and maddening about it is, it is so cheap what they are doing, and it is so effective," said Heather Conley, director of the Europe program at the CSIS think tank in Washington.
Conley said the United States would have to stay engaged.
"We tend to sort of look at one time events that we'll engage and then we get busy elsewhere... This requires sustained American and European engagement, it's a pretty fragile place," she added.
U.S. officials point towards Russian activity in Montenegro as an example of Moscow's meddling in the region.
Last year, Montenegro said a group of Serb and Russian nationalists had a plan to attack state institutions on the day of an election in 2016 and kill then-Prime Minister Milo Djukanovic. The Kremlin has dismissed the accusation as absurd.
