During the final season of The West Wing, Lowe returned to his role of Sam Seaborn, appearing in two of the final four episodes.
That same year, Lowe filmed Stir of Echoes: The Homecoming, the sequel to the 1999 Kevin Bacon thriller Stir of Echoes.
In 2006, it was announced that Lowe would join the cast of Brothers & Sisters for a guest run of several episodes.
In that same year, Lowe filmed his role as a 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.
After leaving the show, Lowe was the star and executive producer of a failed NBC drama, The Lyon's Den (2003). Although Lowe had expressed unhappiness about his decreased role on that show at the time of his departure, he has now repeatedly said that any animosity between them is over and that he was pleased to be working once more with Sorkin, whose talents as a writer Lowe highly regards. Derek Shepherd of Grey's Anatomy, which eventually went to Patrick Dempsey.
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.
In January 2007, ABC announced that Lowe would be staying on Brothers and Sisters as a "special guest star" for the rest of Season 1 after Lowe's initial appearance on the show in November 2006 brought the best ratings and demographic showing for the show since its premiere.
Soon after ABC announced an early Season 2 renewal for Brother & Sisters in March 2007, Lowe announced he would be returning for the show's second season.
One of Lowe's earliest roles came in the 1983 TV film Thursday's Child, for which he received his first Golden Globe Award nomination for Best Supporting Actor in a Series, Miniseries, or Television Film.