While former US president Barack Obama had labelled Merkel his "closest international partner", there has been little known contact between the German leader and Trump since he took office.
Trump's criticism of Germany over issues ranging from its record trade surplus to Merkel's liberal refugee stance, as well as his backing for Britain to leave the European Union, have not gone unnoticed in Berlin.
A month after US Vice President Mike Pence delivered a message to Europe underscoring the importance of transatlantic ties, Tuesday's meeting will be scrutinised for clues on whether Trump fully endorses that message.
The reserved German leader herself underlined that she is travelling to Washington not only as Germany's leader, but also as an envoy of the EU.
"I will of course point out that for us, our country and our membership in the European Union are two sides of the same coin," Merkel said in Brussels ahead of the visit.
The Washington meeting would also allow for "an exchange of bilateral and international topics, and transatlantic ties, as we have always stressed, are very important," added Merkel's spokeswoman Ulrike Demmer.
As in other similar tours, Merkel will be accompanied by an army of business leaders, but this time the delegation faces an uncertain reception as Trump preaches an "America First" policy.
Siemens boss Joe Kaeser and BMW's Harald Krueger will be part of the group, according to news weekly Der Spiegel, and both will likely be trumpeting the thousands of jobs linked to their investments in the US.
Krueger will also be keen to persuade Trump, who has singled out BMW for hefty tariffs if it built a factory in Mexico, to reconsider the threat.
But "if the government is serious about its new tax, the chancellery has already prepared a series of retaliatory measures," said Der Spiegel.
Juergen Hardt, the German government's US coordinator, said Merkel will sound a clear warning against protectionism, and press Washington to keep working towards a free trade deal with the EU.
Leader of the free world?
The meeting will also be closely watched for the dynamics between the two leaders who appear to stand far apart on content and style.
While Merkel is a firm believer in the European Union and globalisation, Trump cheers Britain's departure from the EU and scrapped the TPP free trade deal in his first days in office.
The two also differ on immigration policies - she slammed his ban on citizens from mainly-Muslim countries, while he criticised as "catastrophic" her liberal refugee stance that led more than a million asylum-seekers into Germany.
And while Merkel, a trained physicist, rarely makes public statements deviating from a thoroughly researched text, Trump does not hold back on announcing US policy upheavals in 140-character Twitter messages.
Merkel had already set the tone from the beginning, when in their first phone conversation, she reminded Trump of democratic values while offering cooperation.
That phone call had led some to speculate that she may have taken on the mantel of the "leader of the free world", a title usually reserved for US presidents.
With Trump's latest bid to temporarily close US borders to refugees and citizens from six mainly-Muslim countries, expectations will be high for Merkel to raise human rights issues.
Asked if that is on the German leader's list, Demmer refused to be drawn.
Washington meanwhile suggested that the meeting will be focused on what both sides have in common than their differences.
A senior administration official skirted a question on Trump's criticism of Merkel over her stance on refugees, saying "those are German government decisions".
"The discussions that they will have on this will focus on the areas where we can cooperate," the official said, adding that Trump will reiterate a demand already driven home by Pence for NATO allies to boost defence spending.
The US president will also be "very interested in hearing her insights on what it's like to deal with the Russians" and Merkel's views on resolving the Ukraine conflict, added the official.