- 1821 – Missouri becomes a state
- 1823 – Monroe Doctrine proclaimed
- 1825 – Erie Canal is finally completed
- 1830 – Oregon Trail which comes into use by settlers migrating to the Pacific Northwest.
- 1830 – Indian Removal Act
- 1831 – Nat Turner's revolt
- 1832 – Maria Stewart is the first black American woman to give speech in front of a mixed audience.
- 1832 – Black Hawk War
- 1832 – Department of Indian Affairs established
- 1834 – Slavery debates at Lane Theological Seminary are one of the first major public discussions of the topic.
- 1835 – Alexis de Tocqueville's Democracy in America published.
- 1836 – Arkansas becomes a state.
- 1837 – U.S. recognizes the Republic of Texas
- 1837 – Michigan becomes a state
- 1838 – Forced removal of the Cherokee Nation from the southeastern U.S. leads to over 4,000 deaths in the Trail of Tears.
- 1843 – Emigrants begin their journey along the Oregon Trail.
- December, 1844 – Oregon passes its Black Exclusion Law.
- 1846 – Dred Scott sues for his freedom
- 1846 – The Mexican–American War begins
- 1846 – Iowa becomes a state
- 1848 – The Treaty of Guadalupe Hidalgo ends the Mexican–American War
- 1848 – Wisconsin becomes a state
- 1849 – California Gold Rush begins
- September 9–20, 1850 – The Compromise of 1850, including the notorious Fugitive Slave Act passed
- September 9, 1850 – California becomes a state
- 1853 – Commodore Matthew Perry opens Japan