He's been a close family ally for nearly two decades and spearheaded her victory to a U.S. Senate seat.
De Blasio, elected in 2013 by touting a populist message of bringing together the city, declined on several occasions Sunday to endorse the former first lady, who, along with President Bill Clinton, helped jump-start his political career.
“I think she’s one of the most qualified people to ever run for this office,” De Blasio said on NBC's "Meet the Press." “But we need to see the substance.”
That's a line several liberal Democrats have taken as Clinton embarks on her presidential campaign. They've called for a debate -- not a coronation -- among Democrats ahead of 2016.
So far, however, only a thin list of prospective candidates are weighing a primary challenge to Clinton.
Former Maryland Gov. Martin O'Malley and former Sen. Jim Webb of Virginia say they are seriously considering a run. O'Malley has been trying to run at Clinton from her left, while Webb, if he runs, would challenge her from the right. Both are decidedly long shots, although Clinton and her aides have said they believe they will have to earn every vote.
Sen. Bernie Sanders of Vermont has also talked of challenging Clinton, although he was elected as an independent, not a Democrat.
Among liberals, who make up De Blasio's New York base, those who have kept a distance from Clinton say they want to see a robust primary debate on issues that include the widening gap between the rich and the middle class, equal pay for women and increasing the federal minimum wage.
Economic issues have been a point of concern for some Democrats when it comes to Clinton, who developed strong ties to Wall Street while representing New York in the Senate from 2001 until she became secretary of State in January 2009. Others object to aspects of Bill Clinton's administration, including his centrist economic advisors, his support of free trade and a welfare overhaul that ended a federal guarantee of aid to the poor.
Still, in a recent NBC/Wall Street Journal poll, 87% of liberals who said they plan to vote in a Democratic primary said they could support Clinton.
De Blasio is among a relatively small list of prominent Democrats, who, for now, are holding off on full-throttle support of Clinton.
New York Sens. Chuck Schumer and Kirsten Gillibrand have offered support. They're among more than two dozen senators who have endorsed her candidacy, along with a host of prominent local Democrats across the country, including Lt. Gov. Gavin Newsom in California.
The number of endorsements Clinton has netted from the Senate -- 27 so far -- significantly exceed the single public endorsement she had gotten from a sitting U.S senator at this point in the 2008 campaign, according to FiveThirtyEight.com.
Yet despite that support, the campaign's message will remain steadfast: Clinton is here to work and earn every vote.
"We totally expect this to be a competitive primary," Robby Mook, Clinton's campaign manager, told supporters Sunday evening on a conference call. "We are going to build an organization that can fight tooth and nail for every single vote."