In 2001 Cosgrove did her first acting role as a girl called Lana in the TV series Smallville, and after that had many other small roles in various television series, and appeared in a starring role as Summer Hathaway in the 2003 film School of Rock. But her claim to fame was when she was cast as Megan Parker in the 2004 Nickelodeon TV series Drake and Josh, which gained a massive following. In 2007 she was cast in another Nickelodeon TV series, iCarly as the main character Carly Shay, who makes her own webshow, acting alongside Jennette McCurdy, Jerry Trainor and Nathan Kress.
Cosgrove made her music debut in 2007, singing the theme song for iCarly called Leave It All to Me, which features her Drake and Josh co-star, Drake Bell. On June 10, 2008 the soundtrack to iCarly was released, including Leave It All to Me and three other songs by Cosgrove, including the next singles, the cover of Amy Diamond's song Stay My Baby, and About You Now, originally by the Sugababes, and another track called Headphones On. The sountrack debuted at #28 on the Billboard 200 and has sold over 200,000 copies. She released a new song, a cover of Christmas Wrapping, for the soundtrack to Merry Christmas, Drake and Josh.
It has also been revealed that Cosgrove is in the middle of recording her debut solo album, possibly with a collaboration with the band Boys Like Girls. Regarding her solo album, she said, "...with the iCarly soundtrack, I didn't get to write any of the songs. I just picked songs that meant a lot to me that I really liked. Now, for my own CD, I've been co-writing and getting really into it. It's still pop-rock fun music like the iCarly soundtrack, but I think it's a little more mature. They're love songs and just fun songs about hanging out with your girlfriends." The album probably going to be released in 2009 at some point.
In 2013, Cosgrove confirmed that she is filming two movies: How Could You Do This To Me?, where she plays a girl who feels that the divorce of her parents has improved her life and, when mom and dad appear to be rekindling sparks, she tries to break them up again. The second, Liars (A-E), is about a woman who travels to watch the inauguration of Barack Obama and remember the past and his loves. She also confirmed that she is working on her second studio album.