Lord Frost said the protocol - put in place to prevent a hard border on the island of Ireland - was "not working and needs to change".
He said he worried the UK's proposals would not be agreed by the EU.
Lord Frost said triggering Article 16, which would suspend part of the deal, may end up as "the only way" forward.
Speaking at the Conservative Party conference, Lord Frost said the government "knew [it was] taking a risk" when it agreed to the protocol in the autumn of 2019, claiming his team were "worried right from the start that the protocol would not take the strain if not handled sensitively".
But he said the arrangements were "going to come apart even more quickly than we feared", and support for the protocol had collapsed across Northern Ireland.
"We can still solve these problems," said Lord Frost, pointing to proposals he sent to the EU in July.
"We still await a formal response from the EU... but from what I hear, I worry that we will not get a response that enables the significant change we need," he added.
"So I urge the EU to be ambitious. There is no use tinkering around the edges. We need significant change."
The EU has sent its own proposals to the UK on changes the protocol, but Lord Frost did not mention them in his speech.
Instead he said if the two sides did not come up with a solution, "using the Article 16 safeguard mechanism to address the impact the protocol is having in Northern Ireland...may in the end be the only way to protect our country, our people, our trade and our territorial integrity, the peace process and the benefits to this great UK".
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