More than 1200 "Hands Off!" demonstrations have been planned by more than 150 groups, including civil rights organisations, unions, LBGTQI advocates, veterans and fair-elections activists.
The protests on Saturday are planned for the National Mall in Washington, DC, state capitols and other locations in all 50 states.
The White House did not return an email message seeking comment about the protests.
Trump has promoted his policies as being in the best interest of the US.
Protesters are assailing the Trump administration's moves to fire thousands of federal workers, close Social Security Administration field offices, effectively shutter entire agencies, deport immigrants, scale back protections for transgender people and cut federal funding for health programs.
Musk, a Trump adviser who owns Tesla, SpaceX and the social media platform X, has played a key role in government downsizing as the head of the newly created Department of Government Efficiency.
He says he is saving taxpayers billions of dollars.
Activists have staged nationwide demonstrations against Trump or Musk multiple times since the new administration took power.
But the opposition movement has yet to produce a mass mobilisation like the Women's March in 2017, which brought thousands of women to Washington, DC, after Trump's first inauguration, or the Black Lives Matter demonstrations that erupted in multiple cities after George Floyd's killing in 2020.
Organisers say they hope Saturday's demonstrations will be the largest since Trump returned to office in January.
