Simmons, who was in the second year of a two-year contract, guided Saints to a fifth successive Grand Final last October but has paid the price for the club's worst ever run in the summer era.
Saturday's 12-8 loss at Bradford was their fourth-straight defeat and they have taken just a point from their last five matches, their worst run since 1985.
Simmons' right-hand man Kieron Purtill has also stepped down and Saints have appointed head of performance Mike Rush as acting head coach, with former captain Keiron Cunningham as his assistant
St Helens chairman Eamonn McManus said: "Our season has got off to a difficult start and it is best to make change sooner rather than later.
"We have every faith in Mike Rush and Keiron Cunningham. They each know the club inside out and have all the experience together to take us forward."
The 51-year-old Simmons recently spoke about the pressure on him to deliver silverware to St Helens, whose last trophy success was in 2008 when they lifted the Challenge Cup under Daniel Anderson.
Saints have badly missed England hooker James Roby, who has sat out their last two matches through injury, but their dismal run began with a draw at Hull KR a month ago, followed by a dramatic last-second home defeat by Catalan Dragons.
They have subsequently also lost to Huddersfield, Hull and Bradford and face a Grand Final rematch with Leeds at Langtree Park on Sunday.
McManus added: "I would like to go on record to pay genuine tribute to Royce Simmons. He is a fantastic person and of absolute character and integrity, who has given everything to the club.
"I am sure that everyone at the club joins me in thanking him sincerely for all his work and dedication and to wish him and his family well for the future. Our sentiments are the same with Kieron Purtill. Force of circumstance has reconstituted change."