Taking place in 1789, Thomas Jefferson returns home in America from his time off in France, at which point Hercules Mulligan refers to Jefferson in an attempt to stop Hamilton's financial plan, as in his belief would grant the government excessive power over the people ("What'd I Miss"). Jefferson hears his request and debates with Hamilton over his plan in a heated manner; George Washington privately tells Hamilton that he must find a way to convince Congress of his plan in favor of both parties ("Cabinet Battle #1").
Hamilton returns home to work, at which time Eliza remind him that his son has turned nine years old. At dinner, his son Philip Hamilton performs a rap he composed, which impresses his father and convinces him of his son's literary skill. Angelica tells Hamilton that his best chances would be in convincing Jefferson, his main political enemy, that his financial plan had benefits so that Congress would accept as well. She and Eliza then try to persuade Hamilton to accompany them on a trip upstate to their father's house; however, Hamilton declines, saying he was caught up in work for his plan for Congress ("Take A Break").
While not in the company of family, Hamilton is approached by Maria Reynolds, who tells him her husband James Reynolds is mistreating her and is unfaithful. Hamilton decides to aid Maria, and eventually began an affair. The scandal slips to her husband, who in turn confronts Hamilton and says he will keep the affair a secret if Hamilton agrees to pay him a sum. Hamilton, though scared for his political reputation, accepts the blackmail and continues the affair ("Say No To This").
Hamilton goes to Jefferson and Madison and they discuss his financial plan. He, Madison, and Jefferson come to a compromise: the plan would be put to action if the nation's capital were to be moved from New York to a site closer to Jefferson's home in Virginia, Washington, D.C. Meanwhile, Aaron Burr is envious of the amount of power Hamilton holds over the government and its decisions, wishing he could be of that position ("The Room Where It Happens"). He switches his political party and overthrows Hamilton's father-in-law, Philip Schuyler's seat in the Senate, and is granted more political power as a result. Because he is now against the Schuylers, Burr creates a divide between him and Hamilton ("Schuyler Defeated").
In the second cabinet battle, Jefferson and Hamilton dispute over whether the United States should aid the France in the French Revolution (War of the First Coalition). Washington sides with Hamilton, deciding to stay neutral ("Cabinet Battle #2"). After the argument, Burr, Madison, and Jefferson recollect on how image-worthy it must feel to have Washington on his side always and discuss a plan to ruin Hamilton's political reputation ("Washington On Your Side").
Washington talks with Hamilton and privately announces that he is stepping down from the government. Hamilton retorts that Washington would never be defeated in the campaign for the presidency; Washington replies that he has stepped down from running for president as well. Hamilton is shocked but is convinced by him that it is in the best interests of the nation. The men write a farewell address ("One Last Time"). King George III, in turn, is jubilant upon receiving news that Washington has stepped down, certain that the rebel nation would fall apart under the leadership of John Adams ("I Know Him").
The Federalist Party is brought down by a dispute between Hamilton and John Adams ("The Adams Administration"). Madison, Jefferson, and Burr think they have found a scandal capable of ruining Hamilton's image and charge him with committing treason and pilfering money from the government; however, in truth, they had discovered the transactions of Hamilton's payments catering James Reynolds' blackmail in order to keep his affair with Maria Reynolds secret. Hamilton, knowing the lie spun to dismantle his career was worse than the truth, begs the men not to publicize the scandal and informs them of his affair ("We Know"). Hamilton remembers that being truthful has saved him many times in the past and decides that it is the only way out of his situation ("Hurricane").
Hamilton then publishes his affair to the public in his creation of the Reynolds Pamphlet ("The Reynolds Pamphlet"). When Eliza comes to know of the affair through the publication, she mournfully vows to never look back on everything they had, and "erases herself from the narrative", claiming that in the course of history no one would know her reaction to Hamilton's actions ("Burn").
Years pass after the course events, and their son Philip turns nineteen and graduates from Kings College. He hears about George Eacker publicly degrading Hamilton's reputation and immediately challenges him to a duel. He then asks his father for guidance. Hamilton lends him his pistols and tells him to be safe. Philip counts to ten as his mother taught him, but Eacker shoots him at the count of seven ("Blow Us All Away"). Philip is taken to the doctor, and passes away, Hamilton and Eliza by his deathbed ("Stay Alive (Reprise)"). After Philip's death, the Hamiltons move uptown, where it is calmer and more serene, and Hamilton requests Eliza's forgiveness for everything he has done, to which Eliza accepts ("It's Quiet Uptown").
It is 1800, and president John Adams is defeated in the campaign, after which Thomas Jefferson and Aaron Burr are matched in a tie. The public then asks for whom Hamilton supports, as he has the public's trust and will unbalance the tie. Hamilton replies that though he has never supported Jefferson once, he would now because Burr had switched his loyalties again for person reputation ("The Election of 1800"). After Jefferson's election, Burr is outraged and commences Hamilton to a duel for what he has done ("Your Obedient Servant"). On the morning of the duel, before Hamilton's departure, Eliza calls him back to bed. Hamilton replies gently that he has to leave, and calls her lovingly the "best of wives and best of women" ("Best of Wives and Best of Women").
Hamilton travels to Weehawken, New Jersey with trusted seconds, close to where his son Philip died in his duel. Hamilton willingly "throws away his shot" , but Burr thinks this is unwilling and shoots him, fatally wounding him. He later realizes that even though in terms of the duel he won, he would only be remembered through the course of history as the villain who killed Alexander Hamilton ("The World Was Wide Enough").
The company then proceeds to end the musical, and Eliza sings about "putting herself back in the narrative" and continuing to remember Alexander's legacy, and tells the story of the soldiers who fought by his side. Eliza collects funds for the Washington Monument and raises awareness against slavery. After Alexander's time, Eliza founds the first private orphanage in New York City and helps with the raising of hundreds of children. As she passes, she is shown that her legacy will be protected and passed on as she did for the legacy of Alexander Hamilton ("Who Lives, Who Dies, Who Tells Your Story").