Almost 50 years to the day since John Kennedy declared "Ich bin ein Berliner" and 26 years since Ronald Reagan exhorted "Tear down this wall!" Obama will unveil plans for a one third reduction in Cold War nuclear arsenals.
He will also hold talks with German Chancellor Angela Merkel, with whom he usually has respectful relations, but who is pointedly demanding details on the exact extent of US spy agency surveillance programmes.
Obama will use the speech at the Brandenburg Gate to propose cutting US and Russian strategic nuclear warheads to around 1,000 each, and also seek cuts in tactical nuclear arms stocks in Europe.
"We will seek to negotiate these reductions with Russia to continue to move beyond Cold War nuclear postures," a senior US official said.
It remains unclear whether Russian President Vladimir Putin, with whom Obama had a frosty meeting in Northern Ireland on Monday, will agree to such substantial weapons cuts.
Russia has previously demanded changes to the US missile defense system before agreeing to return to the nuclear agenda.
The president will also commit to attending a nuclear security summit in The Hague next year, and to hosting his own version in 2016 in the last year of his presidency.
Obama inaugurated the first such summit, designed to ensure unsecured nuclear stocks do not fall into the hands of terrorists, in Washington in 2010 and went to a follow-up meeting in Seoul two years later.
His announcement on Wednesday is intended to ensure that his nuclear counterproliferation agenda remains at the center of his foreign policy legacy, following the conclusion of a Strategic Nuclear Arms Reduction Treaty with Russia during his first term.
Though he remains popular in Germany, Obama will struggle to meet the expectations he spun for himself as a presidential candidate, in a speech to 200,000 Berliners in 2008 that made him a political star in Europe.
Since that call for a joint US-European bid to "remake the world" by battling terrorism, global warming, Middle East violence and poverty, Obama has learned the power of the status quo at home and abroad to thwart change.
But frustration will not temper his rhetoric, according to US deputy national security advisor Ben Rhodes.
"Any time a US president speaks in Berlin, it's a powerful backdrop to our post-war
"This is a place where US presidents have gone to talk about the role of the free world.
"With that historical backdrop ... sometimes it's easy to think that history is behind us, essentially. The Wall is down. There's not a threat of global nuclear war. The threats that we do face are far more distant.
"The overarching point that he's going to make is the exact same level of citizen and national activism that was characterized in the Kennedy speech and in the Cold War needs to be applied to the challenges we face now."
In his meeting with Merkel, Obama is under intense pressure to explain the reach and scope of US National Security Agency spying programmes which hoover up data from phone records and the Internet in the United States and abroad.
The programmes, which have special resonance in a nation where snooping operations by the communist Stasi secret police are a painful memory, have triggered alarm across the political spectrum in Berlin.
"I will call for more transparency," said Merkel, who grew up in the communist East in an interview on Monday, adding that Germans wanted to know if their online habits were being spied on by the NSA.
"We have to be clear -- what is being used, what is not being used," she said.
Obama, who arrived in Berlin on Tuesday from the G8 summit in Northern Ireland has said he welcomes public debate on the trade-offs inherent between protecting privacy and citizens from the threat of terrorism.
His speech will come nearly 50 years to the day after Kennedy's famed "Ich bin ein Berliner" address delivered from elsewhere in the city, two years after the erection of the Berlin Wall.
The Gate itself was the backdrop for another climactic moment in Cold War history, when Reagan famously beseeched then Soviet leader Mikhail Gorbachev to "tear down this wall" in 1987.