Weld made the announcement Monday evening in a more than three-minute video, which can be viewed below.
US President Donald Trump is facing a longshot challenge from within his own party ahead of next year's White House election.
Bill Weld, 73, a former governor of MA governor, announced that he would be making the rare move against an incumbent president by calling on "patriotic men and women across our great nation to stand and plant a flag". The video shows clips of his television advertisement during his 1990 campaign for the office.
Libertarian presidential candidate Gary Johnson (R), and his running mate Bill Weld (L), talk to the press before a rally on August 6, 2015 in Salt Lake City, Utah.
But he may struggle to win over a Republican Party that has been reshaped to suit Trump.
Mr Weld's campaign video touts his cross-party credentials as a Republican who was elected in the Democratic stronghold of MA.
The campaign promo ends with the slogan: "A better America Starts Here".
Party leaders have quickly rejected Weld's campaign which make things look hard for him in the long run.
"Any effort to challenge the president's nomination is bound to go absolutely nowhere", the Republican National Committee said in statement.
According to the most recent Gallup poll, 89% of Republican voters approve of the current president.
Mr Trump's campaign said on Sunday it had raised more than $30m in the first quarter of this year.
The 73-year-old is hoping to channel Republican discontent with Trump, despite the president holding a commanding approval rating among registered Republicans and continuing to be favored by the party's core base.
"The RNC and the Republican Party are firmly behind the president", an RNC spokeswoman said in a statement. But who else has a shot at becoming the next president?