Morse was born to a farming family in Verona, Wisconsin, who imbued the political beliefs of Robert M. LaFollette, Sr. in their children; see also, Progressivism and Progressive Party (United States, 1924). He received his Bachelor's degree from the University of Wisconsin in 1923, and his Master's from the same college the next year. He received his degree in law from the University of Minnesota in 1928, and became an assistant professor of law at the University of Oregon in 1930.

Described as an electrifying speaker and having a brilliant legal mind, he quickly became an associate professor and then dean of the university and full professor of law in 1931. Columbia University awarded him a doctorate in law in 1932. He served on many public commissions over following years.

In 1944 he won the Republican primary election for Senator, and the general election that November. Once in Washington, he revealed his progressive roots, to the consternation of his more conservative Republican peers. In protest of Dwight Eisenhower's selection of Richard Nixon as his running mate, he left the Republican Party in 1952. After a term as an independent, he became a Senator for the Democratic Party in 1955. Despite these switches in party allegiance, for which he was branded a maverick, Morse won almost every election for the United States Senate.

In 1964, he was one of only two United States Senators to vote against the Gulf of Tonkin Resolution (Alaska U.S. Senator Ernest Gruening was the other), which authorized further United States involvement in the Vietnam War. Partially as a result, Morse lost his seat in the 1968 election to Bob Packwood by 3,000 votes.

Morse spent the remaining years of his life attempting to regain his seat. He was the Democratic Party nominee for the U.S. Senate in 1972 but lost to incumbent Mark Hatfield. He won his party's Senate primary again two years later, setting up a return match against Packwood, but died before the general election.

Morse's career is detailed in the documentary film The Last Angry Man: The Story of America's Most Controversial Senator, by Christopher Houser and Robert Millis.

In 2006, Morse is slated to receive his name on the new U.S. Courthouse in downtown Eugene, Oregon. In addition he is recognized in the Wayne Morse Commons of the University of Oregon's William W. Knight Law Library. Also housed in the UO Law Center is the Wayne Morse Center for Law and Politics. The Lane County Courthouse in Eugene renovated and rededicated its adjacent Wayne L. Morse Free Speech Plaza in the Spring of 2005, complete with life size statue and quotation pavers. The Morse family's 26 acre Eugene, Oregon property and home, Edgewood Farm, are a National Historic Site. The Morse Ranch, as it is now named, is operated by the City of Eugene as a multi-use park . Interpretive and educational outreach through the site are administered by the non-profit Wayne Morse Historical Park Corporation in order to preserve the Morse Legacy.