Bryson DeChambeau, Brooks Koepka and Spieth are amongst the many high-profile players who will play no further part in this year's Masters.
The former US Open champion followed his first round 76 with an eight-over 80 on day two at Augusta National, finishing on 12-over par and missing the cut by by eight shots.
It continues a miserable run for DeChambeau who has been restricted to only four appearances so far in 2022 - three of them missed cuts - due to a succession of injuries.
In his pre-tournament press conference on Monday, he revealed that he was pegging it up this week against the advice of his doctors and coach, who wanted him to rest in order to let his injuries heal fully.
It is the 28-year-old's first missed cut in The Masters. He remains without a top-20 finish in the opening men's major of the season.
Four-time major champion Brooks Koepka and the 2015 Masters champ Jordan Spieth are also emptying out their lockers.
Koepka went 75-75 to finish on six-over, with Spieth doing likewise after labouring to a four-over 76 on day two. His misadventures included a triple-bogey six at the par-3 12th after dunking two balls in Rae's Creek.
Others going home early include the 2018 Open champion Francesco Molinari and former world No.1 Justin Rose.
Molinari, who led The Masters going into the back nine on Sunday in 2019, had rounds of 78 and 74 to finish on eight-over.
Rose joined him on that mark after a pair of 76s.
Olympic gold medallist Xander Schauffele (+7) is also making an early exit, as are the 2019 US Open champion Gary Woodland (+8), Abraham Ancer (+7) and the heavily-fancied Sam Burns (+5).