2001 bought huge life changes to Ms. McGowan. In January, she announced that her relationship to Manson was over. "There is great love, but our lifestyle difference is, unfortunately, even greater." Rose refused to talk about the break-up publicly for a while but later on said that she couldn't deal with Manson's drug abuse. "I couldn't take his lifestyle. The drugs - more than you could imagine. I realized it wasn't a lifestyle I wanted to be married to. I have never been a rock chick."

On a brighter note, Rose McGowan was offered a two-year contract on the hit WB series Charmed as the long lost witch sister Paige Matthews and she took up on it. Her contract kept getting renewed and every year it did she would cry. Rose said that the biggest positives about starring in a TV series included the steady pay and being able to follow the character for such a long period of time. She was also proud of the fact that Charmed still remains one of the longest running female-run shows. "The coolest thing is that I'm very pro-women and certainly not afraid to call myself a feminist, unlike a lot of women these days. It is not a remotely dirty word and what the best thing about Charmed is that it is completely pro-women, strong women. It might be high heels and mini-skirts but you're still kicking somebody's ass." Most of all, it caused Rose personal growth and gave her the kind of family that she never really had growing up. "Charmed has probably caused more personal growth than I would have thought. I was an extremely undisciplined person. If I didn't like something, I would move. If I didn't like a city, I would leave. Having to work without those parameters... I suppose it is more adult."

Despite the demanding working hours that came with Charmed, Rose managed to film roles in the musical comedy Stealing Bess (2002), Elvis Presley biopic Elvis (2005) and Brian De Palma’s neo-noir The Black Dahlia (2006). In 2003 she also sang vocals on the song "Superfabulous" for BT’s album Emotional Technology, which became a surprise hit. Rose had a three-year relationship with David Zinczenko, the editor of Men's Health magazine. Despite Rose being located in Los Angeles for Charmed and David residing in New York, the couple was able to make their relationship work for several years. They would spend the weekends together, both communing to the opposite sides of the US for each other.

Two years turned into a five-year tour-de-force performance for Rose McGowan and 2006 marked the end for Charmed. The final episode, Forever Charmed, aired on 21st May and gave a happy ending to Paige Matthews and her witchy sisters.