For eight seasons on NBC's Will & Grace, Megan Mullally sashayed blithely through her scenes as Karen Walker, a boozy, pill-popping, New York socialite, tossing off brittle barbs like "Honey, you know what's really funny? Poor people with big dreams." That was then. And that was Karen. These days, the two-time Emmy winner (including the one she won just last week) has shed her character's elitist affectations and is letting her Midwestern roots (she hails from Oklahoma) shine through as host of The Megan Mullally Show, her new daytime gabfest debuting Sept. 18.

"It's entertainment, so I want people to have fun," she says, "but the subtext of the show is to encourage them to remember that everybody's special and everybody has a story to tell." So, in addition to A-list guests like Will Ferrell, look for noncelebs like Tony Peacock, the 2006 National Hollerin' Champion, who will teach Mullally his technique.

Seven shows have been taped so far. "We already have a 'Best of' reel, and it has crazy stuff on it: spit takes, aerial cartwheels, and just in seven shows!" says Mullally.

Still, the transition from sitcom second banana to talk show doyenne hasn't been a total day at the circus. "I've locked myself in the bathroom," says Mullally, 47, of those hectic times before taping when staffers pepper her with rapid-fire instructions. "You have to sit and look at, like, your knee, and take a deep breath and just think, 'Oh, I have a knee. Right, yeah, knees are interesting.'"

Preshow chaos aside, Mullally is confident she's made the right career move. "Everything she does, she does with great gusto," says her mother, Martha. Back in 2003, Mullally got a taste of the talk-show-host life by filling in for an ailing David Letterman. "I had so much fun doing that, and I was so not nervous at all," she says. "I thought, 'Wait a minute, maybe this is something I should be doing.'"

Born in L.A. but raised in Oklahoma City, Mullally was obsessed with talk shows as a kid. "I can remember the camera angle on The Tonight Show and when you could see Johnny [Carson] sitting behind [the guests], and you could tell from the way his head was tilted if he liked it or not," she says.

Now Mullally's getting advice from Johnny's successor and other accomplished chat maestros. "Jay Leno has made a point of taking me aside when I've done his show to sit and gab, and Conan O'Brien has been incredible. Rosie, Merv Griffin, Ellen, Letterman, The View ... I've had a lot of support."

Her husband, actor Nick Offerman, 36, whom the previously married Mullally wed in 2003, has been a source of strength too. After busy days on the set she says, "I do just like to stay home with Nick and the dogs," poodles Willa and Elmo, at their two-bedroom L.A. house.

Meanwhile she tries to keep up with her old Will & Grace castmates, Eric McCormack, Debra Messing and Sean Hayes. Since the finale, "I've seen Deb [who's already booked to appear on the Sept. 26 show] and Sean a few times, and we e-mail back and forth," says Mullally. "Eric, I haven't seen since May. He was doing a play and then his mom passed away, so I've left messages for him," but the two have yet to connect, she says.

But no matter how far she moves from the character she played on Will & Grace, fans still mistakenly address her as Karen. "I don't even notice it, that's the sad part," she jokes. "I once called that lady who wrote Bridget Jones's Diary, Helen Fielding, I called her Bridget and everybody laughed, they thought it was hilarious. I was like, 'Yeah, like people don't call me Karen, freakin' 900,000 times a day?' The joke's on—I don't know who—me, I guess."

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What I Learned from Will & Grace
IGNORE THE NAYSAYERS

I didn't get Will & Grace until I was almost 40. Had I listened to everybody else who kept saying, "Oh, there's too much competition, you'll never get an agent, you'll never get a part, 90 percent of actors are out of work," if I'd listened to that, if everybody listened to that, then nobody would leave the house and the world would come to a crashing halt.

STICK TO YOUR GUNS

What I took away from Will & Grace was confidence. That was the biggest change for me. Now I feel like I can trust my instincts. I would say follow your bliss and persevere.

PAY ATTENTION TO PSYCHICS

When I went up there and accepted the [second] Emmy, I remembered that when I was about 20, a psychic told me I was going to win two Emmys that were going to be like bookends for playing a secretary on a sitcom. And I said, "I'm not going to do sitcoms. I'm a great actress and I'm going to change the world."

Megan's Chat Show Challenge
Talk show guests say—and do—the darndest things. So we asked Mullally how she'd handle these situations:

TOM CRUISE TRAMPOLINES ON YOUR COUCH.

Maybe I'm an idiot, but I thought it was cute. I would just go along with it. Oprah did.

FARRAH FAWCETT SEEMS A BIT OUT OF SORTS.

I would hope to get a heads-up before she came on. But I always identify with hosts like Conan O'Brien. If a guest is going down a wrong road, he will steer it in a different direction. I hope I would be trying to make the guest look good, no matter what.

PRESIDENT BUSH DROPS BY.

I'm not a very political person, so I would be talking about his dogs or cats.

DREW BARRYMORE FLASHES YOU.

I wish she would. That would be fun. I guess I'd flash her right back.