Cleland served in the United States Army during the Vietnam War, attaining the rank of Captain. He was awarded the Silver Star and the Bronze Star for valorous action in combat, including during the battle of Khe Sanh. On April 8, 1968, Cleland was severely wounded when he attempted to pick up a grenade he thought had been dropped by another soldier seconds earlier. He lost both legs and part of one arm when the grenade exploded.

Cleland served from 1971 to 1975 in the Georgia Senate, and became an advocate for affairs relating to veterans. He was the administrator of the United States Veterans Administration under President Jimmy Carter, a fellow Georgian, from 1977 to 1981. He then served 14 years as Secretary of State of Georgia from 1982 to 1996, working closely with his future Senate colleague, Zell Miller. Cleland ran for and was elected to the United States Senate in 1996. The Democratic nomination became available because of the retirement of Sam Nunn. He was defeated while running for a second term in 2002 by Representative Saxby Chambliss. Voters were perhaps influenced by perceptions that Cleland had moved too far to the left in supporting his party's platform, or perhaps by Chambliss ads which featured Osama bin Laden and Saddam Hussein, ads which Cleland supporters claimed questioned his patriotism, though his opponent denied any such insinuation.

Accusations of fraud have been made in a Project Censored article, claiming that "On Nov. 3, 2002, the Atlanta Journal-Constitution poll showed Democratic Sen. Max Cleland with a 49-to-44 point lead over Republican Rep. Saxby Chambliss. The next day, Chambliss, despite trailing by 5 points, ended up winning by a margin of 53 to 46 percent. This was, in other words, an unbelievable 12-point turn around over the course of one day!"

Cleland was originally appointed to serve on the 9/11 Commission but resigned shortly after, claiming that the Bush administration was "stonewalling" and blocking the committee's access to key documents and witnesses. During his time away from politics, Cleland taught at American University.

In 2003, Cleland began working for the presidential campaign of Massachusetts senator (and fellow Vietnam veteran) John Kerry, who later won the Democratic nomination. Cleland often appeared at campaign events with Kerry, and was considered by many to be one of his most important assistants, partly as a symbol of the sacrifices made by soldiers for wars. He went to Bush's Texas ranch to deliver a swift boat ad complaint, but the event failed to have much impact. On July 29, 2004, Cleland introduced Kerry at the Democratic National Convention, making a speech just before Kerry's speech.

Cleland is author of the books Strong at the Broken Places and Going for the Max!: 12 Principles for Living Life to the Fullest. He holds a B.A. in English from Stetson University and a Masters degree in American History from Emory University. He holds honorary doctorate degrees from both institutions.