He plays a marketing exec with a pregnant wife (Jayma Mays) who suddenly find the little blue creatures shacking up in their apartment after being magically whisked to New York and going on the run from evil wizard Gargamel.
Meanwhile, Harris is set to return to his Emmy-nominated role of Barney in CBS' "How I Met Your Mother" in the fall.
Here are five things to know about the actor:
1. He didn't find it hard acting opposite characters he couldn't actually see. In Smurfs, Harris spends a lot of screen time with the little guys, but the actor embraced the challenge. "It was fun," he told movie news site I Am Rogue. "I absolutely love doing the pratfalls, the double takes and the spit takes. I was trying to channel my inner Bill Erwin because he and David Shiner are famous for doing their miming comedy. I had to do a lot of miming comedy in this movie and get knocked over a lot by little creatures that aren't there."
2. He was named one of "Time" magazine's most influential people last year. Joss Whedon, Harris' producer on the web series "Dr. Horrible's Sing-Along Blog," wrote a tribute to the actor for "Time." "Neil loves magic tricks," he wrote. "He's good at them, but his greatest trick may be himself: not just the way he was suddenly all over TV — and other media -- but also that he made it seem like he'd always been there, a charming, Carsonesque presence."
3. He is getting a star on the Walk of Fame this year. The actor joins fellow TV stars Tina Fey, Danny DeVito and Ed O'Neill as the 2011 Walk of Fame inductees.
4. He loves playing Barney but isn't sure he'd do a spinoff. "I always find it kind of douchey when an actor is ready to get off of a nice role in a popular show, so I would never go anywhere near the 'I'm ready to be done with it' sentiment," he told the "Wall Street Journal," calling Barney a once-in-a-lifetime role. "I would do it as long as it still felt relevant. And we certainly have two more seasons, and I don't know if I would jump into a Barney spinoff where I can do it for another 10 years, because there's other things that I'm intrigued by. But I'm loving this ride."
5. He is engaged. Harris revealed last month that he'd been engaged to partner David Burtka, an actor-chef, for a long time. "David and I did propose to each other, but over five years ago!" he tweeted after the New York State Senate passed a law granting gay and lesbian couples the right to marry. "We've been wearing engagement rings for ages, waiting for an available date."
– The Hollywood Reporter