She starred in the fantasy-themed television series Mulawin in 2004. Soon after, she starred as the superheroine Darna in the TV adaptation of the Mars Ravelo comics. When her contract expired on March 2007, Locsin did not renew her contract with GMA Network and signed an exclusive contract with ABS-CBN. Her first project under ABS-CBN was the television series Lobo. Locsin starred in her first box office movie under Star Cinema, Love Me Again, directed by Rory Quintos.
She is currently the lead star in ABS-CBN's Imortal, the sequel of her first ABS-CBN series, Lobo opposite John Lloyd Cruz.