Federal government

• President: Franklin Pierce (D-New Hampshire)
• Vice President: vacant
• Chief Justice: Roger B. Taney (Maryland)
• Speaker of the House of Representatives: Linn Boyd (D-Kentucky)
• Congress: 33rd

January–June

• January 4 – Senator Stephen Douglas introduces a bill to form the Nebraska Territory. The bill sparked major debates related to slavery issues and evolved into the Kansas–Nebraska Act.
• February 14 – Texas is linked by telegraph with the rest of the United States, when a connection between New Orleans and Marshall, Texas is completed.
• February 28 – The Black Warrior Affair: A ship destined for New York City is detained in Havana, Cuba (under Spanish control at the time). The incident strains U.S.–Spanish relations.
• March 20
  • Anti-slavery activists of the Kansas–Nebraska Act meeting at the Little White Schoolhouse in Ripon, Wisconsin form the Republican Party.
  • The Boston Public Library opens to the public.
• March 30 – Battle of Cieneguilla: The U.S. First Regiment of Dragoons attacks a larger force of Jicarilla Apache and Ute Native Americans near present-day Pilar, New Mexico. The Americans are forced to retreat after losing more than half their number.

• March 31 – Commodore Matthew Perry of the U.S. Navy signs the Treaty/Convention of Kanagawa with the Japanese government (the Tokugawa Shogunate), opening the ports of Shimoda and Hakodate to American trade (see History of Japan).
• April 16 – The American packet ship Powhattan is wrecked off the shore of New Jersey with a loss of more than 200 lives.
• May – Elisha Otis publicly debuts his safety elevator at the New York World's Fair.^[1]
• May 24 – Slave Runaway Anthony Burns is arrested in Boston, MA and soon thereafter (June 2) shipped back to Virginia–back into a life of slavery. Abolitionists of the North would be infuriated.
• May 27 – Taiping Rebellion: United States minister Robert McLane arrives at Nanjing aboard the U.S. Navy warship USS Susquehanna.
• May 30 – The Kansas–Nebraska Act is signed into law, creating Kansas Territory and Nebraska Territory, opening new lands, repealing the Missouri Compromise of 1820, and allowing settlers in those territories to determine if they would allow slavery within their boundaries.
• June 10 – The first class of the United States Naval Academy graduates at Annapolis, Maryland.

July–December

• July 4 – Henry David Thoreau delivers his fierce speech, Slavery in Massachusetts in Framingham, MA, harping on American politicians and journalists, all the while calling for action against the injustice of slavery within the Union.
• July 6 – In Jackson, Michigan, the first convention of the Republican Party is held.
• July 8 – An anti-Catholic riot in Bath, Maine, destroys a church used by Irish Catholics.
• July 13 – Bombardment of San Juan del Norte: The USS Cyane attacks San Juan del Norte, Nicaragua.
• August 7–8 – Know Nothings riot against immigrants in St. Louis, Missouri, leading to 10 deaths.^[2]
• August 9 – Walden first published.
• August 19 – Grattan massacre: A group of U.S. Army soldiers in Nebraska Territory are killed by Lakota Sioux warriors after they killed Chief Conquering Bear, starting the First Sioux War.
• September 28 or 29 – Sloop USS Albany (1846) is lost off the coast of Venezuela with all hands.
• October 1 – The watch company founded in 1850 in Roxbury, Massachusetts by Aaron Lufkin Dennison relocates to Waltham to become the Waltham Watch Company, pioneer in the American System of Watch Manufacturing.
• October 9–11 – The controversial Ostend Manifesto is secretly drafted. The document implies that the U.S. should acquire Cuba from Spain by any means necessary.
• October 16 – Abraham Lincoln, in his "Peoria speech", expresses opposition to the Kansas–Nebraska Act, Popular Sovereignty, and slavery in the United States.^[3]
• November 29 – Bleeding Kansas: A pro-slavery Democrat, John Wilkins Whitfield, is elected as the Congressional Delegate for Kansas Territory.
• December 26 – The Treaty of Medicine Creek is signed in Washington Territory. The U.S. acquires land from various Native American tribes and in return creates three reservations.

Undated

• Professor Benjamin Silliman, Jr. of Yale University, using the fractional distillation process developed by his father, Benjamin Silliman Sr, now becomes the first person to fractionate petroleum into its individual components by distillation. Thus, petroleum products like gasoline and kerosene are first produced.
• Waterbury, Connecticut brass manufacturer Benedict & Burnham Manufacturing Company create the department, and eventual independent company, Waterbury Clock Company. This becomes the predecessor of the modern-day Timex Group USA, manufacturer of timepieces.^[4]
• Achulet massacre: More than 65 Tolowa people are killed by settlers in California.

Ongoing

• California Gold Rush (1848–1855)
• Bleeding Kansas (1854–1860)