Metzenbaum, who is Jewish, was born in Cleveland and received a bachelor's degree from Ohio State University in 1939 and a Juris Doctor (J.D.) degree from the same school in 1941. He practiced law in Cleveland before being elected to the Ohio House of Representatives, serving there from 1943 to 1947. He then served in the Ohio Senate from 1947 to 1951. In 1958, he was the campaign manager for U.S. Sen. Stephen M. Young.

In 1970, Metzenbaum ran for the Senate seat of his former employer, Young, defeating John Glenn, the first American astronaut to orbit the earth, in the Democratic primary. But Metzenbaum lost to Robert Taft, Jr. in the general election. Metzenbaum then ran a group of weekly newspapers in the Cleveland area.

In 1974, when Senator William B. Saxbe (R-Ohio) resigned from his seat to accept the nomination as U.S. attorney general, Governor Jack Gilligan appointed Metzenbaum to fill out the remainder of Saxbe's term. Metzenbaum ran for election to the seat, but in a bitter Democratic primary, Metzenbaum lost to Glenn, who won the general election.

In 1976, however, Metzenbaum sought a rematch against Taft. This time he won, riding on Jimmy Carter's coattails. Taft resigned the seat a few days before his term ended, allowing Metzenbaum to be sworn in a few days early and hence have a small edge in seniority over other senators newly elected in 1976. He was reelected in 1982, defeating frequent Republican candidate Paul Pfeifer. In the late 1970s and early 1980s, Glenn and Metzenbaum had strained relations, even though they were both from the same party and the same state. There was a thaw in 1983 when Metzenbaum endorsed Glenn for president.

In 1988, Metzenbaum was opposed by Cleveland mayor George Voinovich. Voinovich accused Metzenbaum of being soft on child pornography. Voinovich's charges were roundly criticized by many, including Glenn, Metzenbaum's old-time rival in the Democratic party and then Senate colleague who now came to Metzenbaum's aid, recording a statement for television refuting Voinovich's charges. Metzenbaum won the election in a landslide, even as President George Bush won Ohio's electoral votes by 11 percent.

Metzenbaum did not run for reelection in 1994. His son-in-law, Joel Hyatt, was nominated by the Democrats to replace him, but Hyatt lost to Lieutenant Governor Mike DeWine, who had been elected as Voinovich's running mate in 1990.

While in the Senate, Metzenbaum was a powerful liberal. He was known as "Senator No" (a nickname shared by Republican Jesse Helms of North Carolina) because the Senate Democrats knew that almost nothing would get through if Metzenbaum opposed it even though he never held an official party leadership post or chaired a committee. Metzenbaum took a particular interest in antitrust and consumer protection issues, often threatening to repeal the exemption from antitrust laws given to Major League Baseball. Since his retirement, however, the issue has gone largely unaddressed. Metzenbaum became well-known for his service on the Senate Judiciary Committee, particularly because of his dedicated efforts to keep stringent antitrust laws and his pro-choice stance on abortion.

Metzenbaum devised a different method for filibustering in the Senate by offering scores of amendments to bills in place of talking one bill to death like his Southern colleagues did during the debate for Civil Rights in the 1950s and 1960s. He is thought to have been the Senator (or his staff) who leaked news about Anita Hill from an FBI Report during hearings for Clarence Thomas' confirmation as a Supreme Court justice.

Metzenbaum is the author of the Howard M. Metzenbaum Multiethnic Placement Act of 1994 (MEPA) (U.S. Public Law 103-82), which prohibits an agency or entity that receives Federal assistance and is involved in adoptive or foster care placements from delaying or denying the placement of a child on the basis of the race, color, or national origin of the adoptive or foster parent, or the child involved.

Since leaving the Senate in 1995, Metzenbaum has served as the chairman of the Consumer Federation of America. Metzenbaum is currently a resident of Florida. The United States Bankruptcy Court in Cleveland, Ohio was named in his honor in 2005.

Metzenbaum's cousin, James Metzenbaum, was a prominent Ohio attorney who wrote a noted text on zoning law and once ran for a seat on the Ohio Supreme Court.