Boris Johnson and Liam Fox have been labelled a "double act of danger" amid calls for Wales to have a separate foreign policy.
A team of diplomats who answer to the Welsh government should be created to prevent Foreign Secretary Mr Johnson being left to speak for the country, Plaid Cymru said.
Assembly Member Steffan Lewis, Plaid's external affairs spokesman, has also proposed creating a "ministry for international affairs" for the Welsh government in an attempt to prevent Westminster from having the greatest influence over Wales's global dealings.
Plaid targeted the two Brexit-backing UK Government ministers despite a majority of Welsh voters supporting Leave - by 52.5% to 47.5% - at last month's EU referendum.
Out of Wales' 22 councils, 17 backed Brexit while only five voted to Remain - despite Wales being heavily funded by the European Union for a number of projects.
Mr Lewis claimed the UK's global reputation will be "damaged" under Mr Johnson while Welsh trade will be "at the mercy" of International Trade Secretary Liam Fox.
He said: "Wales being tied to this double act of danger poses real questions for us as a nation in terms of how we see ourselves in the world, and how we want to be seen by other countries."
Mr Lewis added that post-Brexit "to mitigate the threats to Wales from the new team of isolationist hawks appointed to key international roles in Westminster, we need a dramatic change in Welsh foreign policy".
He went on: "We need a new infrastructure for Welsh foreign policy, backed by a new ministry for international affairs at Welsh government level.
"There is precedent for sub-state governments having significant global roles and reaches such as Quebec in Canada and Flanders in Belgium."