"Tariffs are bad enough on their own. Tariffs married with uncertainty are even worse," Flake, who is not seeking re-election, said on the Senate floor Monday evening.
Trump frequently attacked multilateral trade deals as a presidential candidate, contending that "unfair" trade relationships with allies have hurt U.S. workers and citing hefty U.S. trade deficits as evidence.
And Trump has recently advocated starting a trade war against other nations, which he said are "good" and "easy to win."
On Thursday, Trump signed two executive orders that will enact broad tariffs of 25 percent on steel and 10 percent on aluminum.
The orders were signed over the objections of more than 100 congressional Republicans, who urged Trump in a letter to at least pare back the scope of the tariffs. The Republicans called on Trump to target the tariffs toward "China's unfair practices."
"I understand free trade is sometimes a challenge. I understand that it's a challenge on the campaign trail, certainly," Flake said on Monday.
"It's much easier to point to a shuttered factory," he said, "or some other convenient scapegoat."
But Flake maintained that tariffs will make things worse, not better, for Americans and the U.S. economy.
"You can be pro-growth or pro-tariff, but you cannot be both," he said.