Like Mr Obama, Mrs Clinton will face fierce opposition from a Republican-controlled Congress, but unlike the sitting president she will be one of the least popular figures ever to take office. The window to implement her agenda will be short and the stakes incredibly high.
Mrs Clinton will have to choose her priorities wisely, as the course she charts during the first 100 days may well determine the success or failure of her presidency.
Immigration
No issue has loomed over the 2016 campaign - and laid bare the gulf between the opposing candidates' visions for America - more than immigration.
Mrs Clinton does not plan to build a wall, or assemble a "deportation force". Instead, she wants to implement a pathway to citizenship and shield millions of illegal immigrants from deportation.
Fortunately for the Democratic nominee, the American public prefers her proposals. Two-thirds are open to comprehensive immigration reform, according to Gallup.
She has calculated that a bipartisan agreement is within reach, perhaps one that could even set the stage for compromise on other issues.
Many Republicans in Congress are staunchly opposed, however. Paul Ryan, the speaker of the house, is open to immigration reform but only if it includes tighter border controls and other measures before the path to citizenship is considered.
Mr Obama's attempts at reform fell short. Succeeding where he failed will take an enormous investment of Mrs Clinton's political capital, but would constitute a signature achievement.
Infrastructure
One of Mr Obama's greatest frustrations was that the massive infrastructure programme he promoted for years continued to be blocked in Congress.
He had wagered that rebuilding America's crumbling roads and bridges could win Republican support, but the price tag was too steep and the salesman too unpopular.
Mrs Clinton seems prepared to make the same bet and hope for different results.
She has pledged "the biggest investment in American infrastructure in decades" in her first 100 days, specifically targeting transportation infrastructure and high-speed internet access.
A drive down one of America's motorways or a stopover in one of its airports provides ample evidence that such an investment is necessary, but it will be difficult to find the funding.
Obamacare
Hillary Clinton may not agree that Obamacare is "the craziest thing in the world" as her husband said, but she does think it needs significant updates to function properly.
Republicans are dead set on repealing the law altogether, though. Some believe it is the single most dangerous piece of legislation ever passed, will bankrupt America and lead the country down the path to socialism.
Both sides agree, though, that lower premiums for small businesses and middle class consumers are necessary. She will have to convince Republicans to help improve the law while accepting that it will remain in place.
Equal pay and paid family leave
Mrs Clinton is expected to introduce legislation to narrow the pay gap between men and women and ensure paid leave for new parents.
Her status as the first woman president may help her gather momentum, but both are viewed as Democratic issues which the opposition has little interest in addressing.
Given the likelihood that Mrs Clinton prioritises immigration, or other aspects of her platform, workplace reforms may well fall by the wayside in her first months in office.
Debt-free university tuition
Mrs Clinton's plan to make college education more affordable played a prominent role in her stump speeches. It involves eliminating tuition for students under certain income levels, and reforming student loans to limit future debts.
It was crafted with the help of Bernie Sanders, which could provide an indication of how likely it is to meet the approval of Republicans in Congress.
Her plan to raise the federal minimum wage to $12/hr (£10/hr) will probably face similar difficulties.
No-fly zone in Syria
Mrs Clinton has said she will negotiate with Russia and Syria to implement a no-fly zone and establish safe zones on the ground for civilians.
Her foreign policy tendencies are more hawkish than Mr Obama's, and she has signalled that she will have a more interventionist Syria policy than the man who nominated her to be America's top diplomat.
Mrs Clinton has also said she will invite Benjamin Netanyahu, the Israeli Prime Minister, to Washington after taking office to help repair a relationship that frayed under Mr Obama.
The Cabinet
One of the key moments from Mr Obama's first 100 days was the installation of Mrs Clinton, his former rival, as secretary of state.
Mrs Clinton will make the nominations for her cabinet before even taking office, but the senate will have to confirm them. The confirmation process may provide insight as to just how dead set Congressional Republicans will be on blocking her agenda.
Her chief of staff and national security team will also take office in her first 100 days.
Supreme Court
Mrs Clinton will have the opportunity to make one more nomination, for the vacant seat on the Supreme Court.
Mr Obama nominated Merrick Garland, a moderate, to replace the late Antonin Scalia, but Republicans refused to take up the nomination in an election year.
Mrs Clinton has not pledged to keep Mr Garland in place as the nominee, and may nominate someone younger and more left-leaning for the lifetime appointment.
Under fire from day one
Mrs Clinton has been investigated and interrogated repeatedly by Congressional Republicans over her emails and the Benghazi disaster.
That scrutiny will only increase if she assumes the Oval Office, particularly if the investigation into her handling of classified information is ongoing come January.
"This investigation will continue whether she wins or not," Mike McCaul, chairman of the House homeland security committee, told Fox News. "But if she wins and the investigation goes forward and it looks like an indictment is pending, at that point in time, under the Constitution, the House of Representatives would engage in an impeachment trial, it would go to the Senate and impeachment proceedings and removal would take place."
Mr Trump has gone a step further, contending that Mrs Clinton would face a criminal trial after taking office.
With opponents who not only object to her policies but consider her a criminal, any accomplishments from Mrs Clinton's first 100 days will be hard fought.