Over the past few weeks, in a strategy that has generated little national comment, Barack Obama's advisers have increasingly put female Democratic officials, including Mikulski, out front. Their more prominent role, as the face of the campaign on television and at public events, is designed to counter Palin's appeal and reach out to undecided voters, most of whom are women, while avoiding the charges of sexism that have been lodged against Palin's male critics.
Mikulski, 72, makes it clear there's no love lost between her and the man who chose Palin, even though they are longtime colleagues. She and John McCain served in the House of Representatives together and won election to the Senate on the same day in 1986.
"If John McCain becomes president, I would feel terrible," says Mikulski.
As the first woman elected to the Senate in her own right, Mikulski is an obvious ambassador to female voters. Her urban, ethnic roots and popularity among working-class whites also make her a valuable surrogate in blue-collar communities, where the national ticket is weak.
Mikulski, a seasoned campaigner, has clearly warmed to her emerging part in the presidential contest. During a recent interview in her Senate office, she quips that everyone is fascinated by Palin's "pit-bull one-liners," but "we're in the pits because of their bull."
It's a retort likely to be heard often in coming weeks. Mikulski has already shared the podium with Democratic vice presidential candidate Joe Biden, at a recent northern Virginia rally, and expects to hit the road again once Congress completes work on financial bailout legislation.
She campaigned aggressively for Hillary Clinton during the primaries and now strongly supports Obama, but she gave an admiring assessment of the Republican Party's overnight sensation.
"She's new and she's feisty," says the senator, who knows about feisty, and, like Palin, got her start in local government - on the Baltimore City Council in the 1970s. Palin "is grass roots. I think she has a real ear for what people are thinking and feeling. I think the 'hockey mom' resonates."
Mikulski, who drew more votes than any statewide candidate in history in her re-election in 2004, can also recognize raw talent in politics, and she sees it in Palin.
"She's very good at it, and she's a good speaker, and she has her own charisma, so I would acknowledge that," she says.
But the excitement over Palin was merely "a distraction" from the problems facing the country.
"What Sarah Palin is echoing is the John McCain philosophy and approach, and that is an echo of the George Bush approach," Mikulski says.
She declines to offer a personal assessment of McCain, a man she has worked with at the Capitol for more than a quarter-century. Senate tradition imposes a certain deference that crosses party lines, and in spite of her populist image and ability to project a streetwise demeanor, the state's senior senator is a very much a traditionalist when it comes to that institution.
"You know, when you pick a president of the United States, it's not about personal anecdotes," she says. "It should be about hard data."
She says, as does Obama, that she respects McCain's wartime sacrifices but wants voters to judge the Republican on his record in Washington.
McCain has been a maverick on "process issues" like campaign finance, she says. "But on the substance issues, he's by and large been part of his party's own views. ... He's coming in with the same old ideas."
Mikulski, who expects to be campaigning in Midwest and Northeast states, says Obama should be focusing on jobs, education and other bread-and-butter economic issues if he wants to win more working-class votes. Gaining their support requires "meeting people where they are," she says, "listening to what's going on with their lives" and acknowledging their hopes and fears.
As she spoke, the phones in her outer office were ringing steadily with complaints from constituents about a proposed $700 billion financial bailout. Not surprisingly, Mikulski was among the first in Congress to give voice to a public reaction that gathered strength as the week went along.
"Americans are mad as hell, and they want to know, what about them?" she said in the Senate chamber last Monday.
"Those very same Americans who've worked hard and played by the rules and were prudent investors, prudent savers, prudent citizens are asked to pay the bill for those who didn't."
Mikulski contends that Obama has been improving his standing among working-class whites, though polls show continued resistance.
Racial prejudice, she acknowledges, will cost Obama white votes, but "those are the same people who don't vote for Democrats anyway."
She says a troubled national economy and financial market crisis are leading more voters to support Obama and his "even-keeled way" of approaching problems, rather than McCain's "impulsivity and recklessness."
But the election remains highly competitive. There is a good chance McCain will win and Palin will become the first woman to reach the second-highest office in the land.
As the dean of Senate women, a group that now numbers 16, Mikulski has an intense, and highly personal, stake in breaking the remaining glass ceilings in national life. So how does she feel about the prospect of seeing Palin in a job that, incidentally, would make her the presiding officer of the Senate?
"Well, I don't even go there," replies Mikulski, staring back stonily and refusing to say anything more.