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His last broadcast featured musical guest Neil Young, actors Tom Hanks and Will Ferrell -- the first O'Brien-era "Tonight" guest -- and a lengthy and emotional monologue that saw Conan thank his fans, say goodbye to the network, and urge audiences to keep positive as the show switches hands.
Conan came out to rowdy applause from a crowd that chanted his name, begging the audience to stop as he pointed to his watch. "That's gonna have to last me a while," he said of the ovation. He then quipped that he and the audience have an hour "to steal every single item in this studio."
Later, "The Office" star Steve Carell came out and conducted a mock exit interview with Conan that ended with Carell shredding the host's building ID card.
The comedian asked Conan how he'd rate his NBC experience: "positive, very positive, or extremely positive?" He also asked Conan if he'd ever consider returning to NBC -- a thought Conan deadpanned had "not crossed" his mind.
Conan also joked that NBC could have some fun with the $50 million studio it built him for his "Tonight" run, saying the network could use it as the "site of Tiger Woods' 1st Annual Mistress Reunion" or as "hair and chest oil storage for the 'Jersey Shore' cast."
Between antics and jokes, Conan showed emotion and did not appear bitter about his departure.
"There's been a lot of speculation in the press about what I legally can and can't say about NBC and to set the record straight, tonight I'm allowed to say anything I want," Conan said in the final broadcast, according to a preview published by Access Hollywood.
"Between my time at 'Saturday Night Live,' 'The Late Show' and my brief run here, on 'The Tonight Show,' I've worked with NBC for over 20 years. Yes, we have our differences right now, yes, we're going our separate ways, but this company has been my home for most of my adult life and I'm enormously proud of the work we've done together," Conan said. "And I want to thank NBC for making it all possible. I really do."
Conan called his departure "the hardest thing I ever had to do," and declared that he had "the best job in the world" while thanking his fans for their support.
"Finally, I have something to say to our fans, this massive outpouring of support and passion from so many people has been overwhelming for me — the rallies, the signs, all the goofy outrageous creativity on the Internet, the fact that people have traveled long distances and camped out all night in the pouring rain… Really, here's what all of you have done — you made a sad situation joyous and inspirational. So to all the people watching, I can never ever thank you enough for the kindness to me," Conan said, visibly choked up. "I'll think about it for the rest of my life."
He also showed a serious and philosophical side, urging his viewers to "not be cynical."
"I hate cynicism," he said. "For the record, it's my least favorite quality. It doesn't lead anywhere. Nobody in life gets exactly what they thought they were going to get. But if you work really hard and you're kind, amazing things will happen."
The program ended with a musical performance that included musicians ZZ Top, Beck, Ben Harper, and "Tonight" drummer Max Weinberg, a comic turn from Will Ferrell's "cowbell" character, and Conan himself, rocking out on guitar with the band as the credits rolled.
Jimmy Fallon began his own program, which follows Conan's, with a tribute to O'Brien, singing an emotional ballad after standing in front of Conan's former "Late Night" studio -- now the "Dr. Oz" set -- and declaring "I'll miss you, Conan."
The show marks the end of a public and at times acrimonious battle with Jay Leno and the network over scheduling. It lead to a $45 million deal to part ways with NBC and rumors that the red-haired funnyman will end up hosting a show at Fox. Conan will receive $33 million and his staff $12 million.
Leno is expected to retake the helm of the "Tonight Show" in March after the Winter Olympics in Vancouver. Conan's deal to leave NBC allows him to return to television in September.