The posting was unsuccessful, and Appleton resigned after six months service and returned to the United States to pursue his personal political interests.
In 1851 he was narrowly elected to Congress, representing Maine's 2nd congressional district.
As a Congressman he became noted for his oratorical skills, and was selected to give the obituary address for former Senator and Secretary of State Daniel Webster in 1852.
In 1855 Appleton was sent as diplomatic envoy to London, England to promote United States interests in negotiations to end the Crimean War.
He returned to the United States in 1857 and was appointed as the fourth Assistant Secretary of State, a post he held for the following three years.
As Assistant Secretary he opened discussions with Russia regarding a prospective Alaska Purchase, leading to the United States acquiring that territory in 1867.
Concurrently, he was editor of a pro-Democratic newspaper The Washington Union, but his career was marred by allegations that he misused this position for personal gain.
He was the United States' envoy to Russia from 1860 until his retirement in 1861.
Appleton died on August 22, 1864, and is buried in Portland's Evergreen Cemetery.