He graduated from Millsaps College, Jackson, Mississippi, in 1960. In 1961 he married Lynda Lou Bennett with whom he has two sons and two daughters. From 1961 to 1963, he served in the U.S. Army. He was ordained as a minister of the United Methodist Church in 1964 and served as a pastor until 1977, when he left the pastoral ministry to campaign against pornography and violence in the media. He gained his Master of Divinity (MDiv.) from Emory University's Candler School of Theology in 1965.

Wildmon founded the National Federation for Decency in 1977, and it was renamed the American Family Association in 1988. The AFA claims a membership of 2,558,861 with over 500 local branches. The veracity of these numbers and how many of these members are active participants is unknown.

His son Tim is president of AFA and ran a news organization called Agape Press, which went offline in early 2007, when it merged with AFR News to create One News Now.

Throughout the late 1970s, Wildmon actively protested television shows that he thought promoted immoral lifestyles. He spoke against such programs as Three's Company, M*A*S*H, and Dallas.

Other productions and organizations against which he has campaigned against include Disneyland/Walt Disney World for allowing LGBT community groups to host "gay days," the film The Last Temptation of Christ, Madonna's Like a Prayer, Robert Clark Young's novel One of the Guys, Blockbuster Video for stocking NC-17 rated movies and Pepsi Co..

Up until mid-April 2007, Wildmon hosted the daily radio program AFA Report, which can be heard weekdays on AFR or anytime on AFR's website. Wildmon left the program because he felt he didn't have adequate time to prepare for it each day, and he needed more time to fulfill other duties. He returned to the program in late April 2008, after receiving letters from listeners asking for him to come back, and after expansions in staff and studio space allowed him more preparation time. In early September, however, Wildmon unexpectedly left the program once again, this time for unknown reasons. He also hosted My Turn with Don Wildmon, a short devotional segment, which no longer airs.

Comedian George Carlin mentioned Wildmon in his 1988 HBO special What Am I Doing in New Jersey? claiming that his opinions influenced the Ronald Reagan Administration to regulate television and radio because he heard things on the radio that "he didn't like". He proceeded to claim that Wildmon did not understand the concept of freedom of choice and advised him to look it up in a library "if [he had] any of them left when [he] finished burning all the books".

Wildmon has responded to his critics by pointing out that he never called for any laws to be passed regulating television. He notes that a boycott, by definition, involves freedom of choice. If his members refuse to buy products from companies that sponsor certain television programs, they are exercising freedom of choice.

In 1991, the British film Damned in the USA, directed by Paul Yule, chronicled the battle between Wildmon and artists Andres Serrano and Robert Mapplethorpe. Musician Lou Reed contributed a reworking of his song "Walk on the Wild Side" entitled "Walk on the Wildmon." This documentary got several awards, including the International Emmy for Best Documentary. After a distributor got the rights to show the film in the United States, Wildmon sued the producers for $8 million in damages, claiming he had a contract with the producers that prevented distribution in the USA. A federal court found that Wildmon's contract did not support his claim concerning distribution of the film.

Wildmon was portrayed by actor Tom Anniko in a very brief scene in the 2003 made-for-TV movie The Unauthorized Story of Three's Company.

On August 18, 2009, Tim Wildmon released the news via email that his father had been admitted to the North Mississippi Medical Center in Tupelo over the weekend of August 15—16, with what was thought to be a serious case of meningitis. After running tests, however, doctors determined that he had St. Louis encephalitis, a disease usually contracted from mosquitoes. He spent 121 days in the hospital and rehab, and later underwent surgery for cancer on his left eye.

On March 3, 2010, it was announced that Wildmon was stepping down as chairman of the American Family Association. His son Tim was expected to become the new chairman.