Edward Bates served in the War of 1812 before moving to St. Louis, Missouri Territory, in 1814 with his older brother James, who started working as an attorney. Their eldest brother Frederick Bates was already in St. Louis by that time, where he had served as Secretary of the Louisiana Territory and Secretary of the Missouri Territory.

Bates's private practice partner was Joshua Barton, who was appointed as the first Missouri Secretary of State. Barton became infamous for fighting duels on Bloody Island (Mississippi River). In 1816 Bates was the second to Barton in a duel with Thomas Hempstead, brother of Edward Hempstead, the Missouri Territory's first Congressional representative. The fight ended without bloodshed. Barton was killed in a duel on the island in 1823.

In 1817, the two organized the James Ferry, which ran from St. Charles, Missouri to Alton, Illinois. Easton had founded the latter town, naming it after his first son Alton.

Bates's first foray into politics came in 1820, with election as a member of the state's constitutional convention. He wrote the preamble to the state constitution—an honor that later influenced his fight against the radical Missouri Constitution of 1865. He next was appointed as the new state's Attorney General.

In 1822, Bates was elected to the Missouri House of Representatives. He was elected to the United States House of Representatives for a single term (1827–1829). Next, he was elected to the State Senate from 1831 to 1835, then to the Missouri House from 1835. He ran for the U.S. Senate, but lost to Democrat Thomas Hart Benton.

Bates became a prominent member of the Whig Party during the 1840s, where his political philosophy closely resembled that of Henry Clay. While a slaveholder, during this time, Bates became interested in the case of the slave Polly Berry, who in 1843 gained her freedom decades after having been held illegally in the free state of Illinois for several months.

After the breakup of the Whig Party in the 1850s, he briefly joined the Know-Nothing Party but Bates became a Republican, and was one of the four main candidates for the party's 1860 presidential nomination. He received support from Horace Greeley, who later switched to support Abraham Lincoln. The next year, after winning the election, Lincoln appointed Bates United States Attorney General, an office Bates held from 1861 until 1864. Bates was the first Cabinet member appointed from west of the Mississippi River.

Bates's tenure as Attorney General generally met with mixed reviews. On the one hand, he was important in carrying out some of Lincoln's earlier war policies, including the arbitrary arrest of southern sympathizers and seditious northerners. On the other hand, as Lincoln's policies became more radical, Bates became increasingly irrelevant. Bates disagreed with Lincoln on emancipation and the recruitment of blacks into the Union Army. In 1864, Lincoln nominated Salmon P. Chase to be Chief Justice, an office Bates had wanted. Bates then resigned and was succeeded by James Speed, a Kentucky Lawyer with Radical Republican views.

Bates returned to Missouri after leaving the cabinet. He participated in the conservative struggle against the adoption of the Missouri constitution of 1865. Bates particularly objected to the "ironclad oath" required as a proof of loyalty, and the temporary disfranchisement of rebel sympathizers. He wrote seven essays arguing against the constitution, but it was ratified nonetheless.

Bates then retired from politics, although he commented on political events in the local newspapers. He died in St. Louis in 1869 and was buried at Bellefontaine Cemetery.