Asner was born on November 15, 1929, in Kansas City, Missouri. His Jewish Russian-born parents, Lizzie (née Seliger), a housewife, and Morris David Asner, ran a second-hand shop. He was raised in an Orthodox Jewish family.

Following his military Service, Asner joined the Playwrights Theatre Company in Chicago, but left for New York City before members of that company regrouped as the Compass Players in the mid-1950s. He later made guest appearances with the successor to Compass, The Second City, and is considered part of The Second City extended family. In New York City, Asner played Jonathan Jeremiah Peachum in the Off-Broadway revival of Threepenny Opera, scored his first Broadway role in Face of a Hero alongside Jack Lemmon in 1960, and began to make inroads as a television actor, having made his TV debut in 1957 on Studio One. There were two standout performances on television. The first was as Detective Sgt. Thomas Siroleo in the 1963 episode of The Outer Limits titled "It Crawled Out of the Woodwork", and the second was as the reprehensible ex-premier Brynov in the 1965 Voyage to the Bottom of the Sea episode "The Exile". He made his first film appearance in 1962, in the Elvis Presley vehicle Kid Galahad.

Asner was married to Nancy Sykes from 1959 until 1988. Together they have three children: twins Matthew and Liza, and Kate. In 1987, he had a son named Charles with Carol Jean Vogelman. Asner is a parent and a grandparent of a child with autism and is deeply involved with the autism nonprofit Autism Speaks. He served on the advisory board of a suburban Chicago firm that employs persons with autistic spectrum disorders to test and program software.

Before he landed his role with Mary Tyler Moore, Asner guest-starred in television series including the syndicated crime drama Decoy, starring Beverly Garland, and the NBC western series The Outlaws and Route 66 in 1962 (the episode titled "Welcome to the Wedding") as Custody Officer Lincoln Peers. He was cast on Jack Lord's ABC drama series Stoney Burke and in the series finale of CBS's The Reporter, starring Harry Guardino. He also appeared on Mr. Novak, Mission: Impossible and The Invaders. Asner also played a minor character in children's television show W.I.T.C.H. (Napoleon – Cornelia's younger sister's cat).

Asner is best known for his character Lou Grant, who was first introduced on The Mary Tyler Moore Show in 1970. In 1977, after the series, Asner's character was given his own show, Lou Grant (1977–82). In contrast to the Mary Tyler Moore series, a thirty-minute comedy, the Lou Grant series was an hour-long award-winning drama about journalism. (For his role as Grant, Asner is one of only two actors to win an Emmy Award for a sitcom and a drama for the same role, with the second being Uzo Aduba.) In addition he made appearances as Lou Grant on two other shows: Rhoda and Roseanne. Other television series starring Asner in regular roles include Thunder Alley, The Bronx Zoo and Studio 60 on the Sunset Strip. He also starred in one episode of the western series Dead Man's Gun (1997), as well as portraying art smuggler August March in an episode of the original Hawaii Five-O (1975) and reprised the role in the Hawaii Five-0 (2012) remake. He also appeared as a veteran streetwise officer in an episode of the 1973 version of Police Story.

Asner was acclaimed for his role in the ABC miniseries Roots, as Captain Davies, the morally conflicted captain of the Lord Ligonier, the slave ship that brought Kunta Kinte to America. That role earned Asner an Emmy Award, as did the similarly dark role of Axel Jordache in the miniseries Rich Man, Poor Man (1976). In contrast, he played a former pontiff in the lead role of Papa Giovanni: Ioannes XXIII (Pope John XXIII 2002), an Italian television film for RAI.

Asner served two terms as President of the Screen Actors Guild, in which capacity during the 1980s he opposed US policy in Central America, working closely with the Alliance for Survival. He played a prominent role in the 1980 SAG strike. He has also been active in a variety of other causes, such as the movement to free Mumia Abu-Jamal and the movement to establish California One Care, single-payer health care in California, for which he created a television advertisement. He endorsed Barack Obama during the United States presidential election, 2008. He was formerly a member of the Democratic Socialist Organizing Committee (DSOC) and is a member of DSOC's successor, the Democratic Socialists of America.

The sudden cancellation of Lou Grant in 1982 was the subject of much controversy. The show had high ratings—the level of which should have justified its ongoing presence in primetime (it was in the ACNielsen top ten throughout its final month on the air). However, the CBS television network declined to renew it. It has been Asner's consistent position that his political views, as well as the publicity surrounding them, were the actual root causes for the show's cancellation.

Asner has also had an extensive voice acting career. In 1987, he performed the role of the title character, George F. Babbitt, in the L.A. Classic Theatre Works' radio theatre production of Sinclair Lewis's novel Babbitt. He also provided the voices for Joshua on Joshua and the Battle of Jericho (1986) for Hanna-Barbera, J. Jonah Jameson on the 1990s animated television series Spider-Man (1994–98); Hoggish Greedly on Captain Planet and the Planeteers (1990–95); Hudson on Gargoyles (1994–96); Jabba the Hutt on the radio version of Star Wars; Master Vrook from Star Wars: Knights of the Old Republic and its sequel; Roland Daggett on Batman: The Animated Series (1992–94); Cosgrove on Freakazoid!; Ed Wuncler on The Boondocks (2005–14); and Granny Goodness in various DC Comics animated series. Asner also provided the voice of famed American orator Edward Everett in the 2017 documentary film The Gettysburg Address.

Asner has won more Emmy Awards for performing than any other male actor (seven, including five for the role of Lou Grant). In 1996, he was inducted into the Academy of Television Arts & Sciences Hall of Fame.

Asner became engaged to Producer Cindy Gilmore in 1991. They married on August 2, 1998. Gilmore filed for legal separation on November 7, 2007. Asner filed for divorce in 2015.

He appeared in the mid- to late-2000s decade in a recurring segment on The Tonight Show with Jay Leno, entitled "Does This Impress Ed Asner?".

In 2001, Asner was the recipient of the Screen Actors Guild Life Achievement Award.

Asner served as the spokesman for 2004 Racism Watch. In April 2004, he wrote an open letter to "peace and justice leaders" encouraging them to demand "full 9-11 truth" through the organization 9-11 Visibility Project. In 2011, Asner hosted the Architects & Engineers for 9/11 Truth documentary on the collapse of 7 World Trade Center that concludes that the building was taken down by controlled demolition.

Asner provided the voice of Carl Fredricksen in the Academy Award-winning Pixar film Up (2009). He received great critical praise for the role, with one critic going so far as to suggest "They should create a new category for this year's Academy Award for Best Vocal Acting in an Animated Film and name Asner as the first recipient."

In July 2010, Asner completed recording sessions for Shattered Hopes: The True Story of the Amityville Murders; a documentary on the 1974 DeFeo murders in Amityville, New York. Asner served as the narrator for the film, which covers a forensic analysis of the murders, the trial in which 23-year-old DeFeo son Ronald DeFeo Jr., was convicted of the killings, and the subsequent "haunting" story which is revealed to be a hoax. Also in 2010, Asner played the title role in FDR, a stage production about the life of Franklin Delano Roosevelt; he has subsequently continued to tour the play throughout the country. In January 2011, Asner took a supporting role on CMT's first original sitcom Working Class. He made an appearance in the independent comedy feature Not Another B Movie, and had a small but pivotal role as Billionaire Warren Buffett in HBO's economic drama Too Big to Fail (2011).

From 2011 to 2015, Asner worked with filmmaker Nicole Zwiren on the feature-length documentary Behind the Fear which promotes HIV/AIDS denialism. The film was released in 2016 with Asner as the narrator.

On March 30, 2012, the Screen Actors Guild (SAG) and the American Federation of Television and Radio Artists (AFTRA) completed a merger of equals, forming a new union SAG-AFTRA. Asner was adamantly opposed to such a merger, arguing that the planned merger would destroy the SAG's health plan and disempower actors. Asner and a group of fellow actors and voice-actors, including Martin Sheen and Ed Harris, filed (but later dropped) a lawsuit against SAG President Ken Howard and several SAG vice Presidents, seeking to have the merger overturned, and the two unions separated to their pre-merger organizations. The lawsuit was formally dismissed on May 22, 2012.

Asner co-moderated a United States presidential debate for alternative candidates on October 25, 2016, at the University of Colorado at Boulder along with Christina Tobin.

Asner is a supporter of Humane Borders, an organization based in Tucson, Arizona, which maintains water stations in the Sonoran desert for use by undocumented migrants, with the goal of preventing deaths by dehydration and exposure. He was the master of ceremonies at that organization's volunteer dinner in fall 2017.

Asner has also provided voice-over narration for many documentaries and films of social activism, including Tiger by the Tail, a documentary film detailing the efforts of the Campaign to Keep GM Van Nuys Open and the chair of the organization, Eric Mann, to keep General Motors' Van Nuys Assembly plant running. He has also recorded for a public radio show and podcast, Playing On Air, appearing in Warren Leight’s The Final Interrogation of Ceaucescu’s Dog with Jesse Eisenberg, and Mike Reiss’s New York Story. Asner was the voice-over narrator for the 2016 documentary "Behind the Fear, the hidden story of HIV", directed by Nicole Zwiren, a controversial study on the AIDS debate.