Clinton later issued a slightly different apology in the interview, saying she was "sorry that it has raised all these questions."
The former first lady also posted a personal apology on Facebook
Tuesday night, saying, "I wanted you to hear this directly from me: Yes, I should have used two email addresses, one for personal matters and one for my work at the State Department. Not doing so was a mistake. I'm sorry about it, and I take full responsibility."
She also added, "I know this is a complex story. I could have -- and should have -- done a better job answering questions earlier. I'm grateful for your support, and I'm not taking anything for granted."
It's part of a full-court press by Clinton to move past the problematic issue that's sent her poll numbers tumbling, and seemingly opened the door to a credible challenge by rival Bernie Sanders, and perhaps Vice President Joe Biden.
Though Clinton has taken responsibility for her exclusive use of a private email server during her time as secretary of state, she told The Associated Press on Monday in Iowa that she doesn't need to apologize for her nagging email controversy because "what I did was allowed."
Clinton defended her practices again on ABC, saying that everyone she emailed in the White House and Obama administration knew she used a private account. She also disputed that she ever traded information over email that was marked classified at the time.
The Democratic front-runner got choked up at one point, when speaking of her late mother and how hard it is to campaign "24/7."
"It's something that just demands everything -- physically, emotionally, spiritually," she said. "I can have a perfectly fine life not being president."
It was a moment reminiscent of when she teared up in the days before the New Hampshire primary in 2008, which some outsiders said contributed to her come-from-behind victory in the state.
Clinton also offered praise for potential rival Biden, who is mulling a 2016 bid.
"I think he could be a good president, there's no doubt about that," she said.
In an interview with MSNBC earlier this month, Clinton apologized for the "confusion" around her exclusive use of a private email server as secretary of state and took responsibility for the controversy, but declined to directly apologize for the email set up.
Clinton's aides have argued that she didn't need to apologize, given what she did was allowed by the State Department, but Clinton's answer on Tuesday seems further than she has gone before.
Clinton turned over 55,000 pages of emails to the State Department earlier this year, but the email controversy has not gone away, partly because of a congressional inquiry into the terrorist attacks in Benghazi has also focused on Clinton's email set up.
David Axelrod, a former top campaign adviser to President Barack Obama, told CNN's Wolf Blitzer on "The Situation Room" Tuesday that Clinton's evolving answers on the subject have been costly.
"Her answers have evolved over time and have prolonged this story," said Axelrod, who is a CNN senior political commentator. "She's trying to bring this thing to an end so she can be heard on other subjects, but she needs a consistent answer."