Mildenberger learned the fight trade, growing up in Occupied Germany. A cousin of his father's, a former boxing champion during the Third Reich, began Karl's fistic education; he then joined the boxing program run by FC Kaiserslautern. He eventually displayed enough promise to be sent to Mannheim for training, as Mildenberger lived in the French Sector of the occupation, which forbade the practice of prizefighting; Mannheim, in the American Sector, had no such restriction. Mildenberger lost his first fight for the European Heavyweight title when he was knocked out by Dick Richardson, the Welsh boxer, in one round in April 1962. Karl rebounded with wins over Joe Erskine, Archie McBride, Joe Bygraves and a knockout win over Billy Daniels. Mildenberger then got a draw with highly ranked Zora Folley in April 1964. Later that year, Mildenberger scored a first-round knockout over Sante Amonte to capture the European Heavyweight title. After defending his European title three times, Mildenberger fought Muhammad Ali for the World Heavyweight Title in September 1966. Mildenberger, the first southpaw to fight for the World Heavyweight title, frustrated the champ for most of the fight, but ultimately lost by TKO when the referee stopped the fight at 1:28 of the twelfth round following a flurry of punches by Ali. Years later, Angelo Dundee cited an eighth round punch to the liver area which hurt Ali, whose ability to withstand body blows was legendary.
In 1967, Mildenberger participated in a tournament staged by the World Boxing Association to determine the new heavyweight champion after Ali was stripped of the title for refusing induction into the US military draft. In the first round of the tournament, getting off the deck, he lost to Oscar Bonavena by a clear twelve-round decision. Mildenberger was not the same afterwards, and was knocked out by contender Leotis Martin in seven rounds. Subsequently, in September 1968, Mildenberger's career ended when he lost the European Heavyweight title to Henry Cooper by eighth round disqualification. Mildenberger has said of his timing of retirement, "If I had retained the title, I would have relinquished it. Win, lose or draw, I would have retired, anyway....This was the end. I was unharmed. No terrible things had happened to me." Mildenberger worked as a lifeguard after his retirement from boxing. He died at the age of 80 on 4 October 2018.
