Organizers of Saturday's demonstration in downtown Berlin said some 50,000 protesters from across the country were expected.
The European Union and United States have been negotiating since 2013 on the Trans-Atlantic Trade and Investment Partnership, or TTIP.
Germany's government has pushed the deal, saying it will boost the global economy.
Protesters, organized by the Confederation of German Trade Unions, known by its acronym DGB, worry that an agreement could lower food safety standards and undermine local regulation by giving international arbitration panels the power to rule over disputes.
Resentment towards the trade deal is further fuelled by a general scepticism among Germans towards the United States linked to revelations about US spying on foreign leaders, including Merkel.