Lowe was drawn to the role because of his personal love of politics, and his longstanding personal relationship with Martin Sheen, who was cast as President Bartlet.When the show premiered, Seaborn was considered the lead, and the pilot centered on the character.In June 2006, he was the guest host for an episode in the third series of The Friday Night Project for the United Kingdom's Channel 4.Lowe has also appeared in a televised advertisement for 'Visit California', along with other celebrities including Governor Arnold Schwarzenegger.Despite his two cancelled 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.The year 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.
Thereafter, his film career decreased and he ventured into television, making his breakthrough as Sam Seaborn on the NBC political drama The West Wing (1999–2003), for which he received a Primetime Emmy Award nomination and two Golden Globe Award nominations.
Unhappy with the stories and his lack of screen time in the fourth season, Lowe announced he would leave.
In an episode broadcast on May 16, 2010, his character was part of a multi-vehicle crash involving a large truck and was put into a coma, the storyline was wrapped up in the first episode of the fifth season; Lowe did not appear in the episode.
In addition to his 2001 Emmy nomination for The West Wing, He is of German, English, Irish, Scottish, and Welsh ancestry. , Lowe found out that one of his ancestors, Christopher East, was a Hessian soldier.
His ancestor was fighting under the command of Colonel Johann Gottlieb Rall and was captured at the American victory at Trenton, New Jersey, on the morning of December 26, 1776.