1803年的路易斯安那購買案（Louisiana Purchase）讓農民得以使用重要的密西西比河水路，把法國勢力從美國西部邊界移除，並且提供美國農人一塊廣大的土地。
幾個星期以後，英國和拿破侖統治下的法國之間開戰了。美國當時的收入仰賴嚮歐洲輸出農産品，因此試圖同時對兩個戰爭中的強權出口食物和原料，以及在它們與它們的加勒比海殖民地之間運輸産品來獲利。當這個行為對兩個戰爭國有利的時候，它們便會准許，然而當這個行為無利於他們的時候便予以反對。
當1805年法國海軍在特拉法爾加戰役（Battle of Trafalgar）中被摧毀後，英國希望斷絶法國的海外貿易紐帶，另一方面也是為了報復美國的貿易行為，英國於是對美國海岸實施了封鎖。
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.