Burns was born in Boyertown, Pennsylvania, to Joseph Burns Jr. (1938–2015) and Janet Burns (née Petaccio). He has two sisters. His father served in the U.S. Navy and later became the human resources director of Safeguard Business Systems. He attended Boyertown Area Senior High School in Berks County, graduating in 1992.
Burns played in bands called Sudden Impact US, Nine Pound Truck, and the Ivys (which he has called a "Morrissey rip-off band") while in high school and college. He studied theatre under an acting scholarship at DeSales University in Center Valley, Pennsylvania, in the Lehigh Valley, where he was discovered by an agent. He dropped out of school and moved to New York City to become a professional actor. He lived in a basement apartment near Times Square, finding his first success as a voice-over artist for ads and making appearances on Homicide: Life on the Street and Law & Order.
In 1995, Burns auditioned for Blue's Clues, thinking it was a voice-over role for a game show. He modeled his audition performance after Christopher Walken. He had long hair and an earring. "I was a bit of a skate rat," he said. Initially, the Nickelodeon executives were not supportive of Burns hosting their new show; in subsequent auditions, the show's creators requested that he dress more conservatively. (Burns reported that the creators, in a call-back phone conversation, asked him, "Could you not look like yourself tomorrow morning?") It became apparent, however, that he was the favorite with preschool test audiences. Executive producer and co-creator Traci Paige Johnson reported that of the 100 people they auditioned, Burns was "the realest". As Alice Wilder, Nickelodeon's Director of Research and Development, said: "[T]here was just something about this kid, who was fresh out of Pennsylvania, who just knew where to look in the camera to really talk to kids. He was just right."

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