To provide for her children, Mary Bingham founded the first female academy west of the Mississippi River in Franklin. When the town flooded in 1825, the family moved to a farm in Saline County, not far from present-day Arrow Rock.

During his teenage years, George pursued various occupations, and around 1828 he moved to nearby Boonville. While apprenticed to a cabinetmaker and Methodist minister, he encountered an itinerant portrait painter. Bingham decided to pursue a painting career. With encouragement from friends, the young, self-taught artist began painting portraits in 1833. Three years later, in April, he married Sarah Elizabeth Hutchison, of Boonville. The couple would have four children; Bingham outlived all but one of them.

In early 1837, Bingham painted portraits in Natchez, Mississippi. After studying in Philadelphia in 1838, Bingham returned to Missouri, where he spent a couple of years painting portraits. Active politically, he attended the 1840 Whig convention in Rocheport, where he sketched and painted political banners. Desiring to paint influential political figures, Bingham left Missouri in 1841 for Washington, D.C. The trip resulted from his friendship with James S. Rollins, whom Bingham had painted in 1834. From 1841 to 1844, Bingham painted in Washington; Petersburg, Virginia; and Philadelphia.

Returning to Missouri in 1845, Bingham began an important and productive period of his artistic career. While his family lived in Boonville, he resided in St. Louis, where he painted portraits and genre scenes. The artist shipped four paintings, including Fur Traders Descending the Missouri, to the American Art-Union in New York. That began a profitable seven-year association with the Art-Union, during which time he produced works that caused him to become considered as one of America's greatest genre painters. His scenes of everyday life allowed Easterners to visualize frontier America.

In 1846 Bingham stumped as the Whig candidate for state representative for Saline County. Although he reportedly won the election, his opponent successfully contested the outcome. After successfully campaigning to represent Saline County in 1848, Bingham's personal life was struck by tragedy when his wife died in November, followed a month later by a son's death. Eventually recovering from these tragedies, he married Eliza K. Thomas in September 1849. Bingham then began years of great artistic success with the completion of such important genre canvases as Watching the Cargo and Shooting for the Beef.

Bingham also remained involved in politics and represented Missouri's eighth district at the Whig National Convention in Baltimore in June 1852. Bingham took his wife and daughter to Dusseldorf, Germany, in August 1856, where he painted portraits of Thomas Jefferson and George Washington. The family returned to Missouri in late January 1859, although the artist went back to Germany the next June and stayed for a few months.

The years prior to the Civil War found Bingham a staunch Unionist. In June 1861, he obtained a captaincy in the U.S. Volunteer Reserve Corps, but he resigned his commission and moved to Jefferson City in 1862 to become the state treasurer in the provisional government, an office he held until 1865. While there, he began one of his most important political paintings, Martial Law or Order No. 11.

Union General Thomas Ewing, Jr., had issued Order No. 11 in 1863 to remove from four of Missouri's westernmost counties all people residing farther than one mile from a Union military post in an effort to neutralize Confederate guerrillas. Bingham considered the order unconstitutional and found its harshness repugnant. He determined to vilify Ewing and his directive on canvas.

An unsuccessful congressional candidate in 1866, two years later Bingham was chosen as an elector to the Democratic State Convention. Bingham completed Order No. 11 during the latter part of May 1868 and continued to castigate Ewing for his actions. He executed a second and slightly larger version of the painting in 1870. It is now a part of the State Historical Society's Bingham collection.

Appointed Missouri's adjutant general in 1875, one of Bingham's duties involved evaluating ex-soldiers' claims against the government. In early 1876, he lobbied Congress to provide Missouri with money to pay its state militia for service to the federal government during the war While there, he began his portrait of the sculptress Vinnie Ream.

Bingham returned to Missouri in May 1876. In October his wife, Eliza's mental health required her admittance to the state insane asylum, where she died in November. Also in October, Bingham's ill health forced him to relinquish his post as adjutant general. The following year, Bingham, through Rollins's influence, became the University of Missouri's first professor of art but spent little time actually teaching. At home in Kansas City, he married for a third time, to Martha Livingston Lykins.

Bingham's last paintings, mostly portraits, were completed in 1878-1879 He had never enjoyed robust health and contracted pneumonia in February 1879. Bingham died at his home in Kansas City the following July. Art historians today consider him to be one of the important portrayers of nineteenth-century American life and people.