Willems has joined Newcastle on a season-long loan deal, with an option to make the move permanent at the end of the campaign.
The defender predominantly made his name at PSV and became the youngest player to appear in the European Championships at just 18 years and 71 days when he featured for the Netherlands at Euro 2012.
Frankfurt signed the left-back in 2017 and he was a regular in his first season at the club, but Willems managed just seven Bundesliga starts under Adi Hutter last term.
The 25-year-old has now become Newcastle's second arrival of the close season, following on from the club-record signing of Joelinton from Hoffenheim.
"Jetro brings a wealth of experience into the dressing room and I'm very pleased to have brought him here," manager Steve Bruce told Newcastle's official website.
"He has played at the highest level and is naturally left-footed so he'll give us another strong option on that side."
Willems' arrival is set to be followed by that of Allan Saint-Maximin, with the Nice winger said to have undergone a medical on Friday ahead of a reported £16 million ($19m) deal.
Frankfurt director Fredi Bobic explained that Willems had requested to leave the club, saying the was not happy being just a squad player with the 2018-19 Europa League semi-finalists.
“Jetro was an important part of our squad for two years," Bobic said. "But he was no longer satisfied with his playing role, so we agreed to his request to change."