The US university president Amy Gutmann is the first woman to become her country's ambassador to Germany.
The Senate confirmed the 72-year-old politics professor nominated by President Joe Biden on Tuesday by a majority of 54 to 42.
The daughter of a Jew who fled Nazi Germany will take over the post of ambassador in Berlin, which has been vacant for more than a year and a half.
Biden had already nominated the renowned political scientist, who has headed the elite University of Pennsylvania in the east coast metropolis of Philadelphia since 2004, last July.
Republican senators subsequently blocked confirmation.
The background was in particular the dispute over sanctions against the Baltic Sea pipeline Nord Stream 2.
In mid-January, the Foreign Affairs Committee of the US Senate finally gave the go-ahead for the personnel, and the Senate plenum has now approved it.
Gutmann's official accreditation as ambassador to Germany will be carried out by Federal President Frank-Walter Steinmeier.
Berlin has already approved the posting, the so-called agrément.
Restoration of good transatlantic relations
The post of ambassador in Berlin has been vacant since the departure of ambassador Richard Grenell, appointed by former US President Donald Trump, in June 2020.
Grenell was repeatedly offended in Germany with his often brash announcements and his confrontational demeanor.
In any case, German-American relations had deteriorated significantly during Trump's tenure.
Biden has made restoring good relations with Germany and other historic allies a central concern of his foreign policy.
Gutmann will now be his representative in Berlin.
For the 72-year-old, her posting to Germany is, so to speak, a return to her roots: her father, who came from Feuchtwangen in Franconia, fled with his family from Nazi Germany to India in 1934.
He later moved to the United States, where Amy Gutmann was born.