Calista Flockhart is among the stars who formerly starred on the show
Guiding Light, said to be the world's longest-running soap opera, is coming to an end in September after 72 years.
The show, which launched the careers of Kevin Bacon and James Earl Jones, began as a 15-minute series on NBC radio in 1937, and debuted on CBS TV in 1952.
The daytime soap followed the Lewis, Cooper and Spaulding families in the fictional town of Springfield.
"It's a very sad thing, but these are the times we live in," said Ron Raines who plays villain Alan Spaulding.
Procter & Gamble Productions, which makes the show, informed cast and crew of the news on Wednesday at separate sets in New York and New Jersey.
Cited in the Guinness Book of Records as the world's longest-running TV drama, Guiding Light has struggled to retain audiences, as viewing figures for daytime soaps suffer a sharp decline in the US.
"The numbers are really tough for all of these old dramas," said Raines.
"I don't think any of the other shows want any of us to go off. We're all in this together."
Last year, Guiding Light underwent a dramatic revamp, abandoning its fixed set in favour of portable cameras, to give the show a more modern feel.
Unhappy with the changes to the show, two of its biggest stars, Beth Ehlers and Ricky Paull Goldin, quit to work on rival soap All My Children.
Guiding Light actress Kim Zimmer, also known as Reva Shayne Lewis Cooper Spaulding Lewis Lewis
But the changes failed to significantly improve viewing figures, and CBS has announced the final episode of the soap will air on 18 September.
However, a spokesman said Procter & Gamble will be looking at alternative ways of keeping the show going - possibly finding a new home on cable TV or online.
"For many of us, it was the first show we ever watched," Lynn Leahey, of Soap Opera Digest told The Associated Press.
"It really is heartbreaking to see something like this go away."