Dedeaux was the head baseball coach at the University of Southern California (USC) for 45 seasons. During this tenure, Dedeaux's teams won 11 national titles, including an unprecedented five straight titles from 1970–74, and 28 conference championships. He was named Coach of the Year six times by the Collegiate Baseball Coaches Association and was inducted into its Hall of Fame in 1970. He was named "Coach of the Century" by Collegiate Baseball magazine. In 2006, Dedeaux was one of the 10 initial inductees to the College Baseball Hall of Fame.
Dedeaux invested $500 to start a trucking firm, Dart (Dedeaux Automotive Repair and Transit) Enterprises, which he successfully built into a successful regional business. When his college coach, Sam Barry, entered the United States Navy during World War II, he recommended Dedeaux to take over the team in 1942 for the war's duration. Upon Barry's return in 1946, they served as co-coaches, with Dedeaux running the team each year until Barry finished the basketball season. The arrangement was so successful that USC won the first College World Series in 1948, defeating a Yale team captained by future U.S. President George H. W. Bush.
Following Barry's death in September 1950, Dedeaux became the sole coach and proceeded to build on the early success to establish the strongest program in collegiate baseball. Prior to his retirement in 1986, Dedeaux's teams won 10 additional CWS titles – no other coach won more than 3 until 1997 – including five consecutively (1970–74).
With USC playing its home games at Bovard Field, Dedeaux became known as "The Houdini of Bovard" for its come-from-behind home-field wins. In 1974 USC constructed a new baseball field named Dedeaux Field in honor of the coach.
Dedeaux also served as the baseball coach for actors and ballplayers on the 1989 film Field of Dreams. While Dedeaux was critical of the "phoniness that was in baseball movies", which he acquired working as an extra in the 1948 filmThe Babe Ruth Story, he accepted the task after reading the original novel Shoeless Joe, and brought Buford along to help him coach the cast.Phil Alden Robinson, who directed the film, said the following about Dedeaux:
"All of the ballplayers in the movie were prepped for the film by Rod Dedeaux. He coached at USC for many years, and is a wonderful man, very full of life, energetic, very supportive, just really was very giving of himself and cheerful all the time, was a great spirit to have around. And one day, we were in between setups and I said, 'Hey, coach, what position did you play?' He said, 'I was a shortstop.' I said, 'Really, could you -- were you good?' He got very quiet, and he said, 'I could field the ball.' I said, 'Could you hit?' He said, 'I could hit the ball.' And he was strangely quiet. And I said to him, 'Well, how come you never played in the majors?' And he said, 'I did.' I said, 'Really?' [Dedeaux said] 'Yes, in 1930-something.' I forget what year he said. He was the starting shortstop for the Brooklyn Dodgers. He played one game, broke his back, and that was the end of his career. And I just blanched. I said, 'My God, you're Doc Graham.' He said, 'That's right.' And I said, 'Do you ever think about, "gee, the career I might've had."' And he said, 'Every day.' He said it very quietly. It was very out of character for him, and I was so touched by that. And I did look him up in the Baseball Encyclopedia: He did go, I think, 1-for-4 with an RBI. That was his lifetime stats. So having him be the man who trained all these fellows, including the kid who plays Doc Graham, was very meaningful to me, and I know it was to him, too. It was great to have him around. I think about that often, about what that must have been like, to be good enough to start with a Major League team, and for one unlucky moment, not be able to do -- the rest of your life takes another turn. What he did with that is, he put all of that emotion -- which could have gone into bitterness or regret -- into being a phenomenal coach. He sent more people to the majors than, I think, anybody else in college history. He's an amazing man."