The 67-year-old actor and his co-star Patricia Heaton - who played married couple Ray and Debra Barone on the classic sitcom which ran from 1996 to 2005 - insisted there is no way the show could be revived in a befitting manner.
"No, there won't be a reboot," Romano told the New York Post.
"The obvious is Peter (Boyle) and Doris (Roberts) and one of the kids - they're no longer with us.
"We're all heartbroken. They're a big part of the show, the dynamic."
Boyle - who played Ray's on-screen dad Frank Barone - died aged 71 in 2006, and the TV family's matriarch Roberts (Marie Barone) died aged 90 a decade later.
Child star Sawyer Sweeten, who played Geoffrey Barone - one of Ray's twin sons on the show - tragically took his own life in 2015 aged 19.
"Without them, I don't know what the dynamic is. We love the show too much, we respect it too much to even try to do it," Romano said.
However, he admitted they would "love" to work on an on-screen reunion.
Heaton agreed, as she insisted attempting a revival series would be "a disservice" to the original cast.
"You shouldn't try to go back and redo something that is pretty much perfect. We need to just leave it there and let people enjoy it for what it was," she said.
The show ended when it did because Romano and series creator Phil Rosenthal felt they had "really done all of the stories".
"They have a lot of integrity in that way. The network would have wanted us to go for three more years, but they didn't want to run the show into the ground."
Similarly, Brad Garrett - who played Ray's brother Robert on the show - recently dismissed the idea of a reboot.
"There is no show without the parents. They were the catalyst, and to do anything that would resemble that wouldn't be right to the audiences or to the loyal fan base," he told People magazine.
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