He portrayed a fictional version of himself as the host of the children's television series Blue's Clues from 1996 until 2002, for which he was nominated for a Daytime Emmy in 2001.

[6] 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.

Executive producer and co-creator Traci Paige Johnson reported that of the 100 people they auditioned, Burns was "the realest".

"[9] Blue's Clues premiered on September 8, 1996, on Nick Jr. and was an instant hit due to Burns's performances as much as the show's format.

The former send torrents of e-mail; the latter scrutinize the show with an intensity that might make even Elmo, the red Muppet, blush.

[11] Also, according to Tracy, Burns was not the typical children's television host: "There is nothing syrupy about him—his humor is sometimes borderline offbeat, but never inappropriate for preschoolers.

"[6] Burns went on by saying, "I knew I wasn't going to be doing children's television all my life, mostly because I refused to lose my hair on a kid's TV show, and it was happening, fast.

[27] Burns appeared in videos for the twenty-fifth anniversary of the premiere of Blue's Clues in 2021, including a widely watched Twitter video on Nick Jr.'s Twitter account in which he – in character as the host of the show – explained reassuringly that he had never forgotten the viewers after leaving to go to college, and marveling at how much each of them had experienced since then.

[28][29][30][31][32] Burns worked on material for his first album, Songs for Dustmites, for two and a half years at a small studio in his home in Brooklyn before it was produced by PIAS Records in late 2002.

[6] He posted eleven songs on his webpage and then realizing he needed help with drums and arrangements went to Steven Drozd of the Flaming Lips for advice.

[33] Burns made several appearances on the series beginning in January 2022, playing a Star Trek enthusiast whom the title character meets.

Burns acted in the 2007 horror-comedy film Netherbeast Incorporated with Darrell Hammond and Dave Foley, playing the part of a vampire.

[38] After residing in Williamsburg, Brooklyn, for much of his adult life, Burns told the New York Post in 2020 that he had been living mostly near the Catskill Mountains for the past four years.