Later on the red carpet, Letterman said he was thrilled by the recognition and to visit Obama at the White House.
"It supersedes everything, honestly," he said. "I haven't won that many awards."
During the show, comedian Tina Fey said she grew up watching her mom laugh at Letterman as he brought on "an endless parade of weirdos."
"Who was this Dave Letterman guy?" Fey said. "Was he a brilliant, subtle passive-aggressive parody of a talk show host? Or just some Midwestern goon who was a little bit off? Time has proven that there's just really no way of knowing."
Alec Baldwin offered a Top 10 reasons Letterman was winning the award, including the fact that he didn't leave late night for a six-month stint in primetime — a not-so-subtle dig at rival Jay Leno.
Jimmy Kimmel, who will soon compete head-to-head with Letterman on ABC, said he fell in love with Letterman early in life and even had a "Late Night" cake on his 16th birthday.
"To me it wasn't just a TV show," Kimmel said. "It was the reason I would fail to make love to a live woman for many, many years."
For Buddy Guy, singers Bonnie Raitt, Tracy Chapman and others got most of the crowd on its feet singing Guy's signature "Sweet Home Chicago."
Morgan Freeman hailed Guy as a pioneer who helped bridge soul and rock and roll.
"When you hear the blues, you really don't think of it as black or white or yellow or purple or blue," Freeman said. "Buddy Guy, your blue brought us together."
Robert De Niro saluted Hoffman, saying he had changed acting, never took any shortcuts and was brave enough to be a perfectionist.