The pair will not resume their roles as co-showrunners when the series, which stars Edie Falco, returns for a fifth season.
A search for a new showrunner to work alongside Falco and exec Richie Jackson is already underway, reports Deadline.
"This has been the best job of my life, but the travel, having to spend six months [in Los Angeles] and six months [in New York] and be away from home, took a toll on me," said Wallem.
Brixius added: "Nurse Jackie has been the ride of a lifetime, and for that I am especially grateful to Showtime, Lionsgate and the incomparable Edie Falco for bringing these stories to life.
"After four years, I have decided to come home to LA - even though my heart is at All Saints."
The fourth season of Nurse Jackie drew a final total of 1.1m viewers when it premiered on April 8, up 7% from the third season opener.
The series continues on Sundays at 9/8c on Showtime.
> NBA star Carmelo Anthony to guest star on Nurse Jackie
Watch a trailer for the fourth season of Nurse Jackie below: