In a career that spanned more than seven decades, he performed in such classic films as A Streetcar Named Desire, for which he won the Academy Award for Best Supporting Actor; On the Waterfront; and One-Eyed Jacks. Among other notable film roles were Archie Lee Meighan in Baby Doll, Zebulon Prescott in How the West Was Won, and General Omar Bradley in Patton. His best-known role, though, was on television as Lt. Mike Stone on the 1970s crime drama, The Streets of San Francisco. During the 1970s and 1980s, he was also the spokesman for American Express.

Karl Malden, the eldest of three sons, was born Mladen Sekulovich in Chicago, Illinois on March 22, 1912, he was born on his mother's 20th birthday and was raised in Gary, Indiana. His Bosnian Serb father, Petar Sekulović (1886–1975), worked in the steel mills and as a milkman, and his mother, Minnie (née Sebera) Sekulovich (22 March 1892–15 July 1995), was a Czech seamstress and actress. The Sekulovich family roots trace back to Podosoje near the city of Bileća in Bosnia and Hercegovina, more specifically, in the eastern portion of Herzegovina. Malden spoke only the Bosnian-Croatian-Serbian language until he was in kindergarten and was fluent in the language until his death. Malden's father had a passion for music, and organized a choir. As a teenager, Malden joined the Karageorge Choir. In addition, his father produced Serbian plays at his church and taught acting. A young Malden took part in many of these plays, which included a version of Jack and the Beanstalk, but mostly centered on the community's Bosnian Serb heritage. In high school, he was a popular student and the star of the basketball team (according to his autobiography, Malden broke his nose twice while playing, taking elbows to the face and resulting in his trademark bulbous nose).[6] He participated in the drama department, and was narrowly elected senior class president. Among other roles, he played Pooh-Bah in The Mikado. After graduating from Emerson High School in 1931 with high marks, he briefly planned to leave Gary for Arkansas, where he hoped to win an athletic scholarship, but college officials did not admit him owing to his refusal to play any sport besides basketball. From 1931 until 1934, he worked in the steel mills, as had his father.

He changed his name from Mladen Sekulovich to Karl Malden at age 22. He anglicized his first name by swapping its letters "l" and "a" and making the result, Malden, his last name; then he proceeded to take his grandfather's first name of Karl and make it his first name. This was because the first theatre company he was in wanted him to shorten his name for its marquee. He thought that they wanted to fire him and were using his name as an excuse; although that wasn't the case, he still changed his name to give them no excuse.

Malden often found ways to say "Sekulovich" in films and television shows in which he appeared. For example, as General Omar Bradley in Patton, as his troops slog their way through enemy fire in Sicily, Malden says "Hand me that helmet, Sekulovich" to another soldier. In Dead Ringer, as a police detective in the squad room, Malden tells another detective: "Sekulovich, gimme my hat." In Fear Strikes Out, Malden, playing Jimmy Piersall's father John, introduces Jimmy to a baseball scout named Sekulovich. In Birdman of Alcatraz, as a prison warden touring the cell block, Malden recites a list of inmates' names, including Sekulovich. (Malden's father was not pleased, as he told his son "Mladen, no Sekulovich has ever been in prison!") In On the Waterfront, in which Malden plays the priest, among the names of the officers of Local 374 called out in the courtroom scene is Mladen Sekulovich, Delegate. Perhaps the most notable usage of his real name, however, was in the TV series The Streets of San Francisco. Malden's character in the program, Mike Stone, employed a legman (played by Art Metrano) with that name, who did various errands.