Julian Castro launched his campaign on Saturday, and Tulsi Gabbard has said she will make a formal announcement within a week.
Mr Castro is expected to be the only Latino in the race, and Ms Gabbard is the first Hindu member of Congress.
Both enter what could be a crowded field of Democrats vying to challenge President Donald Trump.
Until now only former congressman John Delaney has formally launched a campaign, more than a year ago.
However, Senator Elizabeth Warren announced last month she was setting up an exploratory committee to consider a run.
Mr Castro made his announcement in his home town of San Antonio, Texas, where he was mayor from 2009 to 2014.
Aged 44 and long seen as a rising star in the party, he served as housing secretary under President Barack Obama and was on the list of Hillary Clinton’s potential running mates for the 2016 election.
Having a Mexican grandmother, he has used his background to criticise Mr Trump’s calls to build a wall to keep out migrants from Latin America.
Launching his bid under the slogan “One nation, one destiny”, he said: “We say no to the construction of the wall and yes to the construction of communities.”
He said his grandmother would have been amazed at his success and that of his brother Joaquin, a member of the US Congress.
“I’ve always believed that with big dreams and hard work, anything is possible in this country,” he told the crowd.
Correspondents say Mr Castro does not have widespread name recognition and may struggle to make an impression in a crowded field.