The 54-year-old will remain in charge for the Cumbrians' final two games of the season against Port Vale and Newport County.
Carlisle can finish no higher than eighth, having previously recorded 20th, 10th and sixth-place finishes under Curle's guidance.
A statement on United's official website read: "Following a meeting with club directors yesterday, Keith Curle has decided to move on and further his career elsewhere, and will therefore leave the club at the end of the current season.
"The directors and staff would like to thank Keith for his contribution over the last three-and-three-quarter years and wish him well for the future."
Carlisle have won just one of their last eight league matches, drawing six of those.