A spokesperson for the one-time Donald Trump lawyer said the 81-year-old has multiple injuries after the crash late on Saturday evening.
Giuliani was being driven in a rented Ford Bronco by his spokesperson Ted Goodman when their vehicle was struck from behind by a Honda HR-V driven by a 19-year-old woman, New Hampshire State Police said in a statement.
Troopers witnessed the crash, which caused both vehicles to hit the highway median and left them "heavily damaged", police said.
Goodman and the 19-year-old suffered "non-life-threatening injuries" and were taken to hospitals for treatment.
Police said they were investigating the crash and no charges had been filed.
Giuliani was taken to a nearby trauma centre and was being treated for a fractured thoracic vertebra, multiple lacerations and contusions, as well as injuries to his left arm and lower leg, according to a statement posted on X by Michael Ragusa, Giuliani's head of security.
Giuliani "sustained injuries but is in good spirits and recovering tremendously," Ragusa said.
"This was not a targeted attack."
Prior to the accident, Giuliani had been "flagged down by a woman who was the victim of a domestic violence incident" and contacted police assistance on her behalf, Ragusa said.
After police arrived, Giuliani continued on his way and his vehicle was hit shortly after pulling onto the highway in a crash that was "entirely unrelated" to the domestic violence incident, Ragusa told The Associated Press in a statement.
"Thank you to all the people that have reached out since learning the news about my Father," Andrew Giuliani, Rudy Giuliani's son, wrote in post on X.
"Your prayers mean the world."
The crash follows some rocky years for the onetime Republican presidential candidate, who was dubbed "America's mayor" for his leadership in New York after the September 11 attacks in 2001.
Giuliani later became President Donald Trump's personal lawyer for a time and a vocal proponent of Trump's allegations of fraud in the 2020 election, won by Joe Biden.
Trump and his backers lost dozens of lawsuits claiming fraud, and numerous recounts, reviews and audits of the election results turned up no signs of significant wrongdoing or error.
Two former Georgia elections workers later won a $US148 million ($A226 million) defamation judgment against Giuliani.
As they sought to collect the judgment, the former federal prosecutor was found in contempt of court and faced a trial over the ownership of some of his assets.
He ultimately struck a deal that let him keep his homes and various belongings, in exchange for unspecified compensation and a promise to stop speaking ill of the ex-election workers.
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