The Democrat, who co-chaired Clinton's Maryland presidential campaign in 2008, has long said she would back her again if she ran for president in 2016, so her early endorsement was not a surprise.
"Whoopee, Hillary is off and running," Mikulski said in a statement. "I'm ready for Hillary. And America is ready for Hillary."
Rep. Donna F. Edwards, a Prince George's County Democrat who is running for Senate in 2016, also applauded Clinton's announcement. If elected, Edwards would be the first African American woman to represent Maryland in the Senate.
"Hillary Clinton recognizes the problems this country faces, and wants to step up and take them on from the position where she can do the most good," Edwards said. "This is exactly how glass ceilings are broken."
"He will make his decision regardless of what other people decide to do," O'Malley spokesman Lis Smith said in a statement released shortly after Clinton's announcement. "The Democratic Party will benefit from a robust issues debate, and -- should Governor O'Malley decide to enter the race -- he will bring one."
So far, O'Malley has approached Clinton gingerly. He has frequently talked about "new leadership" and said last month on ABC's "This Week" that the presidency "is not some crown to be passed between two families." But he declined to criticize Clinton over revelations that she used a private email server as Secretary of State, and he has drawn few policy distinctions with his top opponent.
Clinton dominates polling in early primary states: She received 61 percent of the vote in February survey of Iowa voters by Quinnipiac University. O'Malley barely registered in that poll.
Yet the former governor has been the laying the groundwork for a campaign for years, and Clinton's entrance into the race may well bring additional attention to her potential challengers as well. In what could be read as an early sign of that phenomena, O'Malley's name was mentioned in a Saturday Night Live skit over the weekend. Actress Kate McKinnon, playing Clinton, joked that O'Malley sounded like a character from The Simpsons.