Ferrer, 36, had already announced that New York would represent his final major before quitting for good on home ground in Madrid next year.
His career at the majors ended sooner than he would have wanted when he was forced to quit with a left leg injury leading with a break in the second set.
But the former world number three left Arthur Ashe Stadium with no regrets.
“It was special because I finish my last Grand Slam playing in the centre court with Rafael, a very good friend.
“Sad because I can’t finish the match. But it’s not a problem. I am a lucky man.”
Ferrer, now ranked at 148, shared some of his greatest moments in the same arena as Nadal.
He beat the world number one in New York — just one of six wins in 31 meetings between the two — on his way to a maiden Slam semi-final in 2007.
Nadal got the better of him in the 2013 Roland Garros final which was Ferrer’s only run to the championship match at the majors.
“We shared a lot of important moments in our careers,” said Nadal, a fellow Davis Cup winner for Spain, after his 6-3, 3-4 win on Monday.
“He’s a good friend, a very good person. When he decides to say goodbye, the tour will miss him. The tour loves him.”
Nicknamed ‘The Bulldozer’ for his unrelenting and dogged defence, Ferrer endured numerous highs and lows in his career.
He was locked in a cupboard by a disenchanted coach while he was once so frustrated by the state of his own game, that he briefly quit tennis to work on a building site.
But he collected 27 career titles and helped Spain to the Davis Cup in 2008, 2009 and 2011.
This year, his passion for the Davis Cup burned as bright as ever when he defeated Germany’s Philipp Kohlschreiber 7-5 in the fifth set of the deciding rubber of their quarter-final.
At almost five hours, it was a special victory coming in his home town of Valencia.
But with his ranking at a 16-year low and with a baby son Leo born this year, Ferrer now has other commitments.
“I was happy when I was drawn to play Rafa here, it was a gift play centre court with him.
“My family were here, my wife, my son, close friends. For me, playing my last Grand Slam with the chance to see them here, it was a gift.”