He was born in Havre de Grace located in Harford County, Maryland. Tydings attended the public schools of Harford County, graduated from Maryland Agricultural College (now the University of Maryland, College Park) in 1910. He engaged in civil engineering with the Baltimore and Ohio Railroad in West Virginia in 1911. He studied law at the University of Maryland School of Law, in Baltimore, and was admitted to the bar and commenced practice in Havre de Grace in 1913.

Tyding was elected to the Maryland House of Delegates in 1916, and was Speaker of the House from 1920-1922. He served in the Maryland State Senate during 1922-1923.

He served in the U.S. Army during World War I and was promoted to Lieutenant Colonel and Division Machine-gun Officer in 1918. He served in Germany with the Army of Occupation and was discharged from the service in 1919.

Tydings was elected as a Democrat to the 68th and 69th sessions of the U.S. Congress from the second district of Maryland (March 4, 1923-March 3, 1927), but was not a candidate for renomination in 1926, having become a candidate for the United States Senate. He was elected to the Senate in 1926, 1932, 1938 and 1944 and served from March 4, 1927, to January 3, 1951. During this time he headed a committee to investigate the early claims of Joseph McCarthy and the penetration of the federal government and military by communism. The committee published a report denouncing Joseph McCarthy and his claims as a hoax. When he ran for re-election in 1950, a composite picture of Tydings with a suspected communist he had never even met was circulated. He was subsequently defeated by John M. Butler. He managed to be nominated in 1956 as Democratic candidate for the Senate, but withdrew before the election due to personal health issues.

During his congressional service, Tydings was chairman of the U.S. Senate Committee on Territories and Insular Affairs (73rd through 79th Congresses), the Subcommittee on the Investigation of Loyalty of State Department Employees ("Tydings Subcommittee") (81st Congress), and Chairman of the U.S. Senate Committee on Armed Services (81st Congress).

Millard E. Tydings died at his farm, "Oakington," near Havre de Grace, Maryland. He was buried in Angel Hill Cemetery.

Named in his honor, the Millard E. Tydings Memorial Bridge is located on the John F. Kennedy Memorial Highway. The bridge carries busy Interstate 95 across the Susquehanna River between high bluffs, as the river far below makes its way to nearby Havre de Grace, where it empties into the Chesapeake Bay. Also named in his honor is the Millard E. Tydings Hall at the University of Maryland, College Park, which houses the departments of Government & Politics and Economics.

His son, Joe Tydings, was also a Senator from Maryland from 1965-1971.