His character, White House deputy communications director Sam Seaborn, is set to be written out of the show in the fourth series, which is yet to be filmed.
Although both sides have said the break is amicable, it has been widely reported that Lowe, 38, is unhappy at not being offered a similar wage rise to his colleagues.
Martin Sheen, who plays President Jed Bartlett, has recently seen his fees per episode rise from $45,000 (£28,618) to $210,000 (£133,554), according to Variety.
And co-star Allison Janney, Richard Schiff, John Spencer and Bradley Whitford all secured rises after reportedly threatening to strike.
All four have been nominated for Emmys in the best supporting actor and actress category alongside Dule Hill, who plays Charlie Young and Janel Moloney, who plays Donna Moss.
Lowe and Sheen were eligible for the best male actor category but only Sheen has received a nomination.
Scandal
Originally the most recognisable face in the show, Lowe began the series as the lead actor - securing both higher wages and a lead credit.
But slowly Sheen emerged as the show's kingpin character, surrounded by more of an ensemble cast.
As Sheen's airtime has grown, Lowe's has become smaller.
The West Wing is credited with reviving Lowe's career after a video emerged of him having sex with an underage girl while attending a Democratic National Convention in 1988.
Having been a successful actor during the 1980s in films such as St Elmo's Fire and the Outsiders, his career nosedived following the scandal.
In the UK, Channel 4 is currently screening the second series.
The third series is due to begin on E4 in August.
A special version of the show about a terror alert at the White House screened weeks after 11 September attracted 25 million viewers in the US.