1803年的路易斯安那购买案（Louisiana Purchase）让农民得以使用重要的密西西比河水路，把法国势力从美国西部边界移除，并且提供美国农人一块广大的土地。
几个星期以后，英国和拿破仑统治下的法国之间开战了。美国当时的收入仰赖向欧洲输出农产品，因此试图同时对两个战争中的强权出口食物和原料，以及在它们与它们的加勒比海殖民地之间运输产品来获利。当这个行为对两个战争国有利的时候，它们便会准许，然而当这个行为无利于他们的时候便予以反对。
当1805年法国海军在特拉法尔加战役（Battle of Trafalgar）中被摧毁后，英国希望断绝法国的海外贸易纽带，另一方面也是为了报复美国的贸易行为，英国于是对美国海岸实施了封锁。
George Washington—a renowned hero of the American Revolutionary War, commander-in-chief of the Continental Army, and president of the Constitutional Convention—became the first President of the United States under the new US Constitution. The Whiskey Rebellion in 1794, when settlers in the Pennsylvania counties west of the Allegheny Mountains protested against a federal tax on liquor and distilled drinks, was the first serious test of the federal government. At the end of his second presidential term, George Washington made his farewell address, which was published in the newspaper Independent Chronicle on September 26, 1796. In his address, Washington triumphed the benefits of federal government and importance of ethics and morality while warning against foreign alliances and formation of political parties. His vice-president John Adams succeeded him in presidency; Adams was a member of the Federalist Party. However, the Federalists became divided after Adams sent a peace mission to France despite ongoing disputes with that nation. Thomas Jefferson, a Democratic-Republican, defeated Adams for the presidency in the 1800 election.
The Louisiana Purchase, in 1803, removed the French presence from the western border of the United States and provided US settlers with vast potential for expansion west of the Mississippi River. Slave importation from Africa became illegal in 1808, despite a growing plantation system in many southern states such as North Carolina and Georgia. In response to continued British impressment of American sailors into the Royal Navy, the Congress declared war on Britain in 1812. The United States and Britain came to a draw in the War of 1812 after bitter fighting that lasted until January 8, 1815, during the Battle of New Orleans. The Treaty of Ghent, officially ending the war, essentially resulted in the maintenance of the status quo ante bellum; however, crucially for the US, some Native American tribes had to sign treaties with the US government because of their losses in the war. During the later course of the war, the Federalists held the Hartford Convention in 1814 over concerns that the war would weaken New England. There, they proposed seven constitutional amendments meant to strengthen the region politically, but by the time the Federalists delivered them to Washington, DC, the recent American victories in New Orleans and the signing of the Treaty of Ghent undermined the Federalists' arguments and contributed to the downfall of the party.
The Monroe Doctrine, expressed in 1823, proclaimed the United States' opinion that European powers should no longer colonize or interfere in the Americas. This was a defining moment in the foreign policy of the United States. The Monroe Doctrine was adopted in response to US and British fears over Russian and French expansion into the Western Hemisphere. It was not until the administration of Theodore Roosevelt that the Monroe Doctrine became a central tenet of US foreign policy. The Monroe Dotrine was then invoked in the Spanish-American War as well as later when Nicaragua sought aid from the Soviet Union.
In 1830, Congress passed the Indian Removal Act, which authorized the president to negotiate treaties that exchanged Native American tribal lands in the eastern states for lands west of the Mississippi River. This established Andrew Jackson, a military hero and President, as a cunning tyrant in regards to native populations. The act resulted most notably in the forced migration of several native tribes to the West, with several thousand people dying en route, and the Creeks' violent opposition and eventual defeat. The Indian Removal Act also directly caused the ceding of Spanish Florida and led to the many Seminole Wars.
In its mission to end slavery, the abolitionist movement gained a large following from both black and white races. The American Anti-Slavery Society was politically active from 1833 to 1839 for the government to abolish slavery, but Congress imposed a "gag rule" that rejected any citizen's request against slavery. William Lloyd Garrison, formerly associated with the Society, then began publication of the anti-slavery newspaper The Liberator in Boston, Massachusetts in 1831, and Frederick Douglass, an ex-slave, began writing for that newspaper around 1840 and started his own abolitionist newspaper North Star in 1847.
The Republic of Texas was annexed by president John Tyler in 1845. The US army, using regulars and large numbers of volunteers, defeated Mexico in 1848 during the Mexican-American War. Public sentiment in the US was divided as Whigs and anti-slavery forces opposed the war. The 1848 Treaty of Guadalupe Hidalgo ceded California, New Mexico, and adjacent areas to the United States, about thirty percent of Mexico. Westward expansion was enhanced further by the California Gold Rush, the discovery of gold in that state in 1848. Numerous "forty-niners" trekked to California in pursuit of gold; land-hungry European immigrants also contributed to the rising white population in the west. In 1849 cholera spread along the California and Oregon Trails. It is believed that over 150,000 Americans died during the two cholera pandemics between 1832 and 1849.