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Despite his two canceled TV series and flops like View From the Top and the made-for-TV movie Perfect Strangers during his post – West Wing run, Lowe found success in the TV miniseries genre.

2004 marked his return to this genre ; he had appeared in 1994's The Stand, based on Stephen King's book of the same name.

In 2004, Lowe starred in the TNT remake of the Stephen King miniseries Salem's Lot which was the highest rated cable program of that summer and the highest ratings TNT original programming had at the time.

In 2005, Lowe starred in the miniseries Beach Girls on the Lifetime network, based on the Luanne Rice novel of the same name.

The series premiere received the highest ratings for a movie premiere in Lifetime history.

In that same year, Lowe filmed his critically acclaimed role as super movie agent in the 2006 independent film Thank You for Smoking.

In 2006, he filmed The Perfect Day for TNT, in which he took a pay cut to film in New Orleans in order to help the hurricane ravaged area.

That same year, Lowe filmed Stir of Echoes: The Homecoming, the " sequel " to the 1999 Kevin Bacon thriller Stir of Echoes.