The play has two acts, telling Hamilton's story through major events in his life and American history. It tells Hamilton's life from beginning to end along with various other characters such as Marquis De Lafayette, Aaron Burr, John Laurens, Hercules Mulligan, Elizabeth Schuyler Hamilton, Angelica Schuyler, Phillip Hamilton and former presidents George Washington, James Madison, Thomas Jefferson and Peggy Schuyler.
The musical begins with the company summarizing Alexander Hamilton's early life as an orphan on the island of Nevis ("Alexander Hamilton"). After arriving in New York in 1776, Hamilton meets Aaron Burr, John Laurens, Marquis de Lafayette, and Hercules Mulligan ("Aaron Burr, Sir"), and impresses them with his rhetorical skills ("My Shot"). They affirm their revolutionary goals to each other ("The Story of Tonight"). Angelica, Eliza, and Peggy are then introduced ("The Schuyler Sisters"). Samuel Seabury warns everyone about the Congress, but Hamilton disagrees and tries to counter Seabury ("Farmer Refuted"). King George then insists on his authority ("You'll Be Back"). During the New York and New Jersey campaign, Hamilton accepts a position as George Washington's aide-de-camp ("Right Hand Man"), instead of field command.
Burr convinces Hamilton to marry a Schuyler ("A Winter’s Ball"). Hamilton meets, falls in love with, and marries Elizabeth Schuyler ("Helpless"), as her sister Angelica suppresses her feelings for the sake of their happiness ("Satisfied"). After the wedding, Hamilton, Laurens, Lafayette and Mulligan drink together, while the three poke fun at Hamilton for getting married. Burr walks in on the group, unexpected by Hamilton to be attending. Burr congratulates Hamilton on his position as aide to camp of Washington; Hamilton confesses that he would much rather have Burr's position on the battlefield ("The Story of Tonight (Reprise)"). Burr reflects on Hamilton's swift rise while considering his own career as more cautious ("Wait For It").
Conditions are worsening for the continental army, and Hamilton's constant pleading to Washington for a command continues to be shot down. Washington grants a command to General Charles Lee, who is clearly unfit to be leading one. After being fired by Washington, Lee goes on a tirade against Washington, claiming him to be unfit to lead. Though Hamilton wishes to challenge Lee, he is commanded not to by Washington. Since Hamilton is unable to challenge Lee, Laurens does ("Stay Alive") and thus duels Lee, with Hamilton and Burr as their seconds. Laurens injures Lee, who in turn yields ("Ten Duel Commandments"). Hamilton is temporarily suspended by Washington ("Meet Me Inside") over the duel, and is sent home. There, Eliza reveals that she is pregnant with her first child, and asks Hamilton to simply slow down to take in what has happened in their lives ("That Would be Enough"). After Lafayette convinces France to get involved on the colonists' side ("Guns and Ships"), he urges Washington to call Hamilton back to help plan the final Siege of Yorktown. Washington agrees but explains to Hamilton—who is convinced he should die a martyr and a hero in war—that he should be careful with his actions, because whatever he does will be known for ages to come ("History Has its Eyes on You"). Hamilton agrees to join, and reflects that he now has something to live for (a wife and a child on the way), and will give up on his efforts to die in war. At the Siege of Yorktown, Hamilton meets up with Lafayette to take down the British, revealing that Mulligan was recruited as a spy, helping them figure out what to do to trap the British and win the war ("Yorktown (The World Turned Upside Down)").
Soon after the victory at Yorktown, Hamilton's son, Philip is born, while Burr has a daughter, Theodosia ("Dear Theodosia"). Hamilton receives word that his friend Laurens has been killed in a seemingly pointless battle, and throws himself into his work ("Tomorrow There'll Be More of Us"). He co-authors The Federalist Papers and is selected as Secretary of the Treasury by newly elected President Washington. Angelica moves to London with her new husband ("Non-Stop").
Thomas Jefferson returns to America from being the U.S. ambassador to France ("What'd I Miss"). In 1789, Jefferson and Hamilton debate the latter's financial proposals at a Cabinet meeting. Washington pulls Hamilton aside, and tells him to figure out a compromise to win over Congress ("Cabinet Battle #1").
Eliza and her family—along with Angelica, back from London—travel upstate during the summer, while Hamilton stays home to work on the compromise ("Take a Break"). Hamilton begins an affair with Maria Reynolds, making him vulnerable to her husband's blackmail ("Say No To This"). Hamilton, Jefferson and James Madison create the Compromise of 1790 over a private dinner, exchanging Hamilton's financial plan for placing the country's permanent capital on the Potomac River. Burr is envious of Hamilton's sway in the government and wishes he had similar power ("The Room Where It Happens").
In another Cabinet meeting, Jefferson and Hamilton argue over whether the United States should assist France in its conflict with Britain. This decision is not subject to congressional approval, and Washington ultimately agrees with Hamilton's argument for remaining neutral ("Cabinet Battle #2"). In the wake of this, Jefferson, Madison, and Burr decide to join forces to find a way to discredit Hamilton in Washington's eyes ("Washington on your Side"). Washington decides to retire from the presidency, and Hamilton assists in writing a farewell address ("One Last Time").
John Adams becomes the second President and fires Hamilton, who publishes an inflammatory critique of the new president as a response ("The Adams Administration"). In the face of accusations of speculation of government funds by Jefferson, Madison, and Burr—and out of fear that his affair with Maria Reynolds will be used against him in his political career ("We Know")—Hamilton chooses to publicize his affair ("Hurricane") in the Reynolds Pamphlet ("The Reynolds Pamphlet"), damaging his relationship with Eliza ("Burn"). Their son Philip dies at the age of 19 in a duel with George Eacker due to a critical speech given by Eacker about Alexander ("Blow Us All Away"/"Stay Alive (Reprise)"), causing a reconciliation between Alexander and Eliza ("It's Quiet Uptown").
Hamilton's endorsement of Jefferson in the presidential election of 1800 ("The Election of 1800") results in further animosity between Hamilton and Burr, who challenges Hamilton to a duel via an exchange of letters ("Your Obedient Servant"). Hamilton writes his last letter in a rush while Eliza tells him to go back to sleep (“Best of Wives and Best of Women”). During the duel, both Burr and Hamilton fire at each other after ten paces, with Hamilton intentionally missing his shot. Hamilton dies as a result, with Eliza and Angelica at his side. Burr laments that even though he survived, he is cursed to be remembered as the villain who killed Hamilton ("The World Was Wide Enough"). The musical closes with a reflection on historical memory, showing how Eliza kept Hamilton’s legacy alive ("Who Lives, Who Dies, Who Tells Your Story").